PubNeph papers Free papers Detection of IL-17 and IL-23 in Plasma Samples of Children with Autism. ä-/-ä 2008; 4 (2): 114-20
Interleukin-23 (IL-23) is a survival factor for a newly described population of T lymphocytes, namely Th-17 cells, that secrete IL-17, tumor necrosis factor- alpha (TNF?) and IL-6. It has been shown that Th-17 cells are a pathogenic T cell subset involved in autoimmune and chronic inflammatory diseases. Based on the increasing evidence of immune dysfunction in autism, including possible autoimmune and inflammatory processes, we hypothesized that Th-17 cells, a T cell lineage that has not been previously examined in this disorder, may be altered in autism. To assess the potential role, if any, of Th-17 cells in autism, we analyzed plasma samples obtained from children ranging in age from 2-5 years with a diagnosis of autism and age-matched typically developing controls for the presence of IL-17 and IL-23 cytokines. Plasma samples from 40 children with autism including 20 children with a regressive form of autism, 20 with early onset and no regression and 20 typically developing age-matched control children were analyzed for IL-17 and IL-23, under the hypothesis that altered number and function of Th-17 cells would directly correlate with altered levels of IL-17 and IL-23 in the plasma. In this study, we were able to demonstrate that IL-23 cytokine levels were significantly different in children with autism compared with age-matched controls, a finding primarily driven by children with early onset autism. In contrast, there were no statistical differences in IL-17 levels autism compared with age-matched typically developing controls. This is the first study to report altered IL-23 production in autism. The decreased plasma IL-23 production observed in children with autism warrants further research as to its affect on the generation and survival of Th-17 cells, a subset important in neuroinflammatory conditions that may include autism.
*27688738* 27688738 Medicinal mushroom: boon for therapeutic applications. 3 Biotech 2018; 8 (8): ä
Medicinal mushrooms are higher fungi with additional nutraceutical attributes having low fat content and a trans-isomer of unsaturated fatty acids along with high fibre content, triterpenes, phenolic compounds, sterols, eritadenine and chitosan. They are considered as the unmatched source of healthy foods and drugs. They have outstanding attractive taste, aroma and nutritional value, so are considered as functional food, which means they are beneficial to the body not only in terms of nutrition but also for improved health. Medicinal mushrooms and their extract have a large number of bioactive components called secondary metabolites. The presence of polysaccharide ?-glucans or polysaccharide?protein complexes content in mushroom extract have great therapeutic applications in human health as they possess many properties such as anti-diabetic, anti-cancerous, anti-obesity, immunomodulatory, hypocholesteremia, hepatoprotective nature along with anti-aging. The present review focuses on the comprehensive account of the medicinal properties of various medicinal mushrooms. This will further help the researchers to understand the metabolites and find other metabolites as well from the mushrooms which can be used for the potential development of the drugs to treat various life-threatening diseases.
*30073119* 30073119 Methionine attenuates the intensity of rheumatoid arthritis by downregulating NF-?B and iNOS expression in neonatal rats. 3 Biotech 2018; 8 (7): ä
The present study investigated the anti-arthritic effects of methionine in neonatal rats. Rats were divided into four groups, with six rats in each group. The rats were administered methionine (150- or 300-mg/kg body weight) orally for 45 consecutive days. The expression levels of catalase, superoxide dismutase (SOD), reduced glutathione (GSH), lipid peroxidation, glutathione peroxidase (Gpx), prostaglandin E2 (PGE2), matrix metalloproteinase-3, uric acid, nitric oxide (NO), ceruloplasmin, inducible nitric oxide synthase (iNOS), and nuclear factor (NF)-?B were determined in rheumatoid arthritis-induced neonatal rats. The levels of SOD, catalase, Gpx, and GSH were substantially reduced in control rats, while the levels of other parameters were increased in control neonatal rats. However, methionine supplementation significantly increased (more than 40%) the levels of SOD, catalase, Gpx, and GSH in neonatal rats. The levels of lipid peroxidation, uric acid, ceruloplasmin, NO, and PGE2 were significantly reduced following methionine supplementation. Furthermore, NF-?B mRNA expression was substantially reduced up to 51.7% in the 300-mg/kg methionine group, whereas the mRNA expression of iNOS was reduced up to 43.5% in the 300-mg/kg methionine group. NF-?B protein expression was substantially reduced up to 45.8% in the 300-mg/kg methionine group, whereas the protein expression of iNOS was reduced up to 45.4% in the 300-mg/kg methionine group. Taken together, these data suggest that methionine supplementation was effective against rheumatoid arthritis.
*30002993* 30002993 Inhibitory effects of Lepidium sativum polysaccharide extracts on TNF-? production in Escherichia coli-stimulated mouse. 3 Biotech 2018; 8 (6): ä
The present study was designed to study the quantitative effects of extraction time, temperature and solvent to sample ratio on the yield of Lepidium sativum polysaccharides (LSP) using a Box?Behnken design. The activities of the optimized LSP extract were then tested in an in vivo experimental system of Escherichia coli (E. coli)-induced endotoxin shock. The optimal polysaccharide extraction conditions were established by the equation of regression and evaluation of the response surface contour plots: extraction time 5.2 h; temperature 95 °C and ratio of water to raw material 31.89 mL/g. Subsequently, an in vivo endotoxin shock was induced in mice with a single E. coli i.p. injection. Septic mice showed a substantial raise in the levels of tumor necrosis factor alpha (TNF-?) in plasma, whereas mice treated with LSP after E. coli injection showed considerable lower plasma levels of TNF-? (P?0.05). These results suggest that LSP have beneficial effects when administered to mice with endotoxin shock by diminishing the pro-inflammatory response. The systemic activity of LSP indicated that the extract has a significant inhibitory effect against E. coli-induced inflammation by reducing the circulating levels of TNF-?. Further studies are warranted to explore the clinical implications of such observations.
*29881664* 29881664 l-Asparaginase: a feasible therapeutic molecule for multiple diseases. 3 Biotech 2018; 8 (6): ä
This note highlights our understanding and thinking about the feasibility of l-asparaginase as therapeutics for multiple diseases. l-asparaginase enzyme (l-asparagine amidohydrolase, EC 220.127.116.11) is prominently known for its chemotherapeutic application. It is primarily used in the treatment of acute lymphoblastic leukemia in children. It is also used in the treatment of other forms of cancer Hodgkin disease, lymphosarcoma, acute myelomonocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, reticulosarcoma and melanosarcoma (Lopes et al. Crit Rev Biotechnol 23:1?18, 2015). It deaminates l-asparagine present in the plasma pool causing the demise of tumor cell due to nutritional starvation. The anti-tumorigenic property of this enzyme has been exploited for over four decades and evidenced as a boon for the cancer patients. Presently, the medical application of l-asparaginase is limited only in curing various forms of cancer.
*29872609* 29872609 Synthesis of gold nanomaterials and their cancer-related biomedical applications: an update. 3 Biotech 2018; 8 (2): ä
Recently, the advances in the synthesis of new types of nanomaterials have created several opportunities in drug delivery and targeted therapy applications. Among the various nanostructures, gold nanostructures with controllable physical and chemical properties have received attention for various biomedical uses, including sensing of biomolecules, in vitro and in vivo bioimaging (as advanced contrast agents for photothermal and bioimaging techniques), photothermolysis of cancer cells, and targeted drug delivery. The attractive properties of gold nanomaterials, particularly, anti-angiogenic properties, are highly useful in a variety of cancers studies. In addition, they can bind many proteins and drugs and can be actively targeted to cancer cells over-expressing cell surface receptors and they are biocompatible in nature with a high atomic number, which directs to greater absorption of kilovoltage X-rays and provides greater contrast than standard agents. In this review, we have summarized the synthesis, structure and functionalization of gold nanostructures, and their biomedical applications with special reference to cancer studies.
*29430374* 29430374 Design of peptide-based epitope vaccine and further binding site scrutiny led to groundswell in drug discovery against Lassa virus. 3 Biotech 2018; 8 (2): ä
Lassa virus (LASV) is responsible for an acute viral hemorrhagic fever known as Lassa fever. Sequence analyses of LASV proteome identified the most immunogenic protein that led to predict both T-cell and B-cell epitopes and further target and binding site depiction could allow novel drug findings for drug discovery field against this virus. To induce both humoral and cell-mediated immunity peptide sequence SSNLYKGVY, conserved region 41?49 amino acids were found as the most potential B-cell and T-cell epitopes, respectively. The peptide sequence might intermingle with 17 HLA-I and 16 HLA-II molecules, also cover 49.15?96.82% population coverage within the common people of different countries where Lassa virus is endemic. To ensure the binding affinity to both HLA-I and HLA-II molecules were employed in docking simulation with suggested epitope sequence. Further the predicted 3D structure of the most immunogenic protein was analyzed to reveal out the binding site for the drug design against Lassa Virus. Herein, sequence analyses of proteome identified the most immunogenic protein that led to predict both T-cell and B-cell epitopes and further target and binding site depiction could allow novel drug findings for drug discovery field against this virus.Electronic supplementary material: The online version of this article (10.1007/s13205-018-1106-5) contains supplementary material, which is available to authorized users.
*29430345* 29430345 Human leukocyte antigen (HLA-F) polymorphism is associated with chronic HBV infection. 3 Biotech 2018; 8 (1): ä
Human leukocyte antigen (HLA)-F has been involved in immune regulation of infectious diseases. However, the role of HLA-F polymorphisms in hepatitis B infection outcomes remains unclear. Here, we aimed to determine HLA-F polymorphism implication in chronic HBV. Genotype analysis was performed for three single nucleotide polymorphisms (SNPs) of HLA-F and one SNP of HLA-E using PCR-SSP, in 252 Tunisian patients with chronic HBV infection stratified according to their HBV DNA levels (140 patients with low HBV DNA levels < 2000 IU/mL and 112 patients with high HBV DNA levels ? 2000 IU/mL) and 240 healthy controls (CTRL). The three HLA-F SNPs (HLA-F01:02, -F01:03 and -F01:04) have the same allelic and genotypic frequencies in patients and in CTRL. We reported a low HLA-F01:02 and F01:04 allelic frequencies in the Tunisian population; however, high HLA-F01:03 allele frequencies were observed (17%). A significant association was found between the HLA-F01:03 allele and decreased level of HBV DNA (P = 0.02 OR 0.56, 95% CI 0.35?0.92). No significant differences were observed in haplotype distribution between patients and CTRL. A significant association of HLA-F01:03 with the level of HBV DNA suggests an important role of HLA-F in HBV replication control.
*29354360* 29354360 Phytochemicals as potential antidotes for targeting NF-?B in rheumatoid arthritis. 3 Biotech 2017; 7 (4): ä
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune destructive arthropathy prevalent among people in the age group of 40?70 years. RA induces severe pain, swelling and stiffness of joints resulting in bone damage. RA leads to reduced life expectancy when left untreated. RA is characterized by synovial hyperplasia, infiltration of inflammatory cells resulting in formation of pannus. Synovial hyperplasia is mediated by proinflammatory cytokines, notably IL-1 and TNF-?. NF-?B is a predominant transcription factor in amplifying the inflammatory response. The translocation of activated NF-?B into the nucleus triggers the transcription of several genes that induce proinflammatory cytokine production. The inhibition of NF-?B translocation aids blocking the activation of proinflammatory cascades. The quest for more effective and side-effect free treatment for RA unveiled phytochemicals as efficacious and promising. Phytochemicals have been a source of therapeutic substances for many ailments from ancient times. Their therapeutic ability helps in developing potent and safe drugs targeting immune inflammatory diseases driven by NF-?B including RA. This review highlights the importance of NF-?B inflammatory cascade in RA so as to elucidate the crucial role of phytochemicals that inhibit the activity of NF-?B.
*28721679* 28721679 Comparative genomic analysis of Mycobacterium neoaurum MN2 and MN4 substrate and product tolerance. 3 Biotech 2017; 7 (3): ä
The microbial bioconversion of sterols can afford valuable steroid precursors, such as 4-androstene-3,17-dione (AD) and androsta-1,4-diene-3,17-dione (ADD). The Mycobacterium neoaurum MN4 mutant strain can produce AD in high yield and can tolerate a higher concentration of the substrate phytosterol than the parent strain M. neoaurum MN2. In order to further investigate the mechanisms underlying the enhanced substrate and product tolerance, we performed a genomic analysis of the MN2 and MN4 strains. The genomes were sequenced using a high-throughput approach and analyzed using software for genome assembly, gene prediction and functional annotation, KEGG (Kyoto Encyclopedia of Genes and Genomes) annotation, COG (cluster of orthologous) group cluster analysis, GO cluster analysis, and SNP detection and annotation. Based on comparative genomics, 184 mutations were identified in MN4, the average variant rate of 1 variant every 27,249 bases, with a TS/TV value of 0.5877 and missense mutations in one key sterol degradation genes (ChoM1) and four side chain degradation genes that encode enzymes catalysing ?-oxidation. The results suggest the high AD yield might be due to mutation of ChoM and genes encoding FadE, FadB and FadA ?-oxidation enzymes. This study provides a theoretical basis for further functional genomics analysis and heterologous production of M. neoaurum MN2 secondary metabolites.Electronic supplementary material: The online version of this article (doi:10.1007/s13205-017-0818-2) contains supplementary material, which is available to authorized users.
*28664368* 28664368 Plant-derived antimicrobials to fight against multi-drug-resistant human pathogens. 3 Biotech 2017; 7 (3): ä
Antibiotic resistance is becoming a pivotal concern for public health that has accelerated the search for new antimicrobial molecules from nature. Numbers of human pathogens have inevitably evolved to become resistant to various currently available drugs causing considerable mortality and morbidity worldwide. It is apparent that novel antibiotics are urgently warranted to combat these life-threatening pathogens. In recent years, there have been an increasing number of studies to discover new bioactive compounds from plant origin with the hope to control antibiotic-resistant bacteria. This review attempts to focus and record the plant-derived compounds and plant extracts against multi-drug-resistant (MDR) pathogens including methicillin-resistant Staphylococcus aureus (MRSA), MDR-Mycobacterium tuberculosis and malarial parasites Plasmodium spp. reported between 2005 and 2015. During this period, a total of 110 purified compounds and 60 plant extracts were obtained from 112 different plants. The plants reviewed in this study belong to 70 different families reported from 36 countries around the world. The present review also discusses the drug resistance in bacteria and emphasizes the urge for new drugs.
*28660459* 28660459 Salicornia: evaluating the halophytic extremophile as a food and a pharmaceutical candidate. 3 Biotech 2016; 6 (1): ä
Food insecurity is a major issue in current scenario where a large section of mankind is at risk of insufficient diet. As food productivity has its limits, the prospecting of unutilized or underutilized flora as food candidates is collectively recognized as a sustainable option. In the past decade, a number of obscure plants have been identified to be rich in dietary components and deemed fit for integration into the food platter. This review discusses a candidate Salicornia, belonging to family Amaranthaceae. This halophyte has a broad geographical distribution, and phytochemical profiling has indicated its food relevance. An array of functional nutrients as fibers, polyphenols, and flavonoids have been detected in Salicornia. Though high salt, oxalate and saponin content in the plants are anti-nutrients, they can be removed to justify usage of Salicornia as a ?sea vegetable?. Apart from culinary relevance, medicinal attributes like immunomodulatory, lipid-lowering, antiproliferative, osteoprotective, and hypoglycemic render this lesser-known marsh plant significant for phytochemical studies. This appraisal is expected to be useful towards further research and popularization of this extremophile halophyte.
*28330174* 28330174 Purification and characterization of RGA2, a Rho2 GTPase-activating protein from Tinospora cordifolia. 3 Biotech 2016; 6 (1): ä
Rho GTPases activating protein 2 (RGA2) is primarily involved in the modulation of numerous morphological events in eukaryotes. It protects plants by triggering the defense system which restricts the pathogen growth. This is the first report on the isolation, purification and characterization of RGA2 from the stems of Tinospora cordifolia, a medicinal plant. The RGA2 was purified using simple two-step process using DEAE-Hi-Trap FF and Superdex 200 chromatography columns, with a high yield. The purity of RGA2 was confirmed by SDS-PAGE and identified by MALDI-TOF/MS. The purified protein was further characterized for its secondary structural elements using the far-UV circular dichroism measurements. Our purification procedure is simple two-step process with high yield which can be further used to produce RGA2 for structural and functional studies.Electronic supplementary material: The online version of this article (doi:10.1007/s13205-016-0400-3) contains supplementary material, which is available to authorized users.
*28330155* 28330155 Modulation of TLR2, TLR4, TLR5, NOD1 and NOD2 receptor gene expressions and their downstream signaling molecules following thermal stress in the Indian major carp catla (Catla catla). 3 Biotech 2015; 5 (6): 1021-30
Toll-like receptors (TLRs) and nucleotide binding and oligomerization domain (NOD) receptors are pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and play crucial role in innate immunity. In addition to PAMPs, PRRs recognize endogenous molecules released from damaged tissue or dead cells [damage-associated molecular patterns (DAMPs)] and activate signaling cascades to induce inflammatory processes. In the aquatic environment, large variation in seasonal and diurnal water temperature causes heat and cold stresses in fish, resulting in tissue injury and mortality of fish. In the Indian subcontinent, catla (Catla catla) is an economically important freshwater fish species and is prone to thermal stresses. To investigate the response of pattern recognition receptors in thermal stress, we analyzed TLRs (TLR2, TLR4 and TLR5) and NOD (NOD1 and NOD2) receptors gene expression in catla following heat and cold stress. Analysis of tissue samples (gill, liver, kidney and blood) of the thermal stressed and control fish by quantitative real-time PCR (qRT-PCR) assay revealed significant (p < 0.05) induction of TLR2, TLR4 and NOD2 gene expression in majority of the tested tissues of the treated fish as compared to the control. The expression of TLR5 and NOD1 gene was also induced in the heat and cold stressed fish, but mostly restricted in the blood. The downstream signaling molecule of TLR and NOD signaling pathway viz., MyD88 (myeloid differentiation primary response gene 88) and RICK (receptor interacting serine-threonine protein kinase-2) was also induced in the thermal stressed fish suggesting the engagement of TLR and NOD signaling pathway during thermal stress.
*28324409* 28324409 Antioxidant activity and structural features of Cinnamomum zeylanicum. 3 Biotech 2015; 5 (6): 939-47
The antioxidants in food materials have recently attracted researchers? attention because many reports have shown that the oxidative stress is closely related to the aging process of the cells and acts as a trigger to various diseases including cancer. Since reactive oxygen species (ROS) is involved in initiating and promoting several diseases such as cancer and cardiovascular events, this study was designed to evaluate the antioxidant capacity of pectic polysaccharides extracted from the bark of Cinnamomum zeylanicum, locally known as Daruchini. An arabinogalactan (A), one partly methyl esterified galacturonic acid (B) and a neutral glucan (C) were isolated. The glucan is made up of ?-(1 ? 3)-linked glucopyranosyl residues and has a molecular mass of 7 kDa. The arabinogalactan is highly branched and has an average molecular mass of 40 kDa. The in vitro antioxidant capacity of the fractions was studied by ferric reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. The arabinogalactan (A) showed the highest potential followed by the uronic acid (B) and glucan (C). Taken together, these findings demonstrate that these polysaccharides could be used as natural antioxidants by the food industry.Electronic supplementary material: The online version of this article (doi:10.1007/s13205-015-0296-3) contains supplementary material, which is available to authorized users.
*28324396* 28324396 Plant terpenes: defense responses, phylogenetic analysis, regulation and clinical applications. 3 Biotech 2015; 5 (2): 129-51
The terpenoids constitute the largest class of natural products and many interesting products are extensively applied in the industrial sector as flavors, fragrances, spices and are also used in perfumery and cosmetics. Many terpenoids have biological activities and also used for medical purposes. In higher plants, the conventional acetate-mevalonic acid pathway operates mainly in the cytosol and mitochondria and synthesizes sterols, sesquiterpenes and ubiquinones mainly. In the plastid, the non-mevalonic acid pathway takes place and synthesizes hemi-, mono-, sesqui-, and diterpenes along with carotenoids and phytol tail of chlorophyll. In this review paper, recent developments in the biosynthesis of terpenoids, indepth description of terpene synthases and their phylogenetic analysis, regulation of terpene biosynthesis as well as updates of terpenes which have entered in the clinical studies are reviewed thoroughly.
*28324581* 28324581 Kinetics of rapamycin production by Streptomyces hygroscopicus MTCC 4003. 3 Biotech 2014; 4 (5): 523-31
Research work was carried out to describe the kinetics of cell growth, substrate consumption and product formation in batch fermentation of rapamycin using shake flask as well as laboratory-scale fermentor. Fructose was used as the sole carbon source in the fermentation media. Optimization of fermentation parameters and reliable mathematical models were used for the maximum production of rapamycin from Streptomyces hygroscopicus MTCC 4003. The experimental data for microbial production of rapamycin fitted well with the proposed mathematical models. Kinetic parameters were evaluated using best fit unstructured models, viz. Andrew?s model, Monod model, Yano model, Aiba model. Andrew?s model showed a comparatively better R2 value (0.9849) among all tested models. The values of maximum specific growth rate (?max), saturation constant (KS), inhibition constant (Ki), and growth yield coefficient (YX/S) were found to be 0.008 (h?1), 2.835 (g/L), 0.0738 (g/L), and 0.1708 (g g?1), respectively. The optimum production of rapamycin was obtained at 300 rpm agitation and 1 vvm aeration rate in the fermentor. The final production of rapamycin in shake flask was 539 mg/L. Rapamycin titer found in bioreactor was 1,316 mg/L which is 52 % higher than the latest maximum value reported in the literature.
*28324387* 28324387 Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin. 3 Biotech 2014; 4 (1): 1-12
An entomopathogenic fungus, Cordyceps sp. has been known to have numerous pharmacological and therapeutic implications, especially, in terms of human health making it a suitable candidate for ethno-pharmacological use. Main constituent of the extract derived from this fungus comprises a novel bio-metabolite called as Cordycepin (3?deoxyadenosine) which has a very potent anti-cancer, anti-oxidant and anti-inflammatory activities. The current review discusses about the broad spectrum potential of Cordycepin including biological and pharmacological actions in immunological, hepatic, renal, cardiovascular systems as well as an anti-cancer agent. The article also reviews the current efforts to delineate the mechanism of action of Cordycepin in various bio-molecular processes. The study will certainly draw the attention of scientific community to improve the bioactivity and production of Cordycepin for its commercial use in pharmacological and medical fields.
*28324458* 28324458 Designing a Resilience Program for Critical Care Nurses. AACN Adv Crit Care 2017; 28 (4): 359-65
Background: Workplace stress can affect job satisfaction, increase staff turnover and hospital costs, and reduce quality of patient care. Highly resilient nurses adapt to stress and use a variety of skills to cope effectively. Objective: To gain data on a mindfulness-based cognitive therapy resilience intervention for intensive care unit nurses to see if the intervention program would be feasible and acceptable. Methods: Focus-group interviews were conducted by videoconference with critical care nurses who were members of the American Association of Critical-Care Nurses. The interview questions assessed the feasibility and acceptability of a mindfulness-based cognitive therapy program to reduce burn-out syndrome in intensive care unit nurses. Results: Thirty-three nurses participated in 11 focus groups. Respondents identified potential barriers to program adherence, incentives for adherence, preferred qualifications of instructors, and intensive care unit-specific issues to be addressed. Conclusions: The mindfulness-based cognitive therapy pilot intervention was modified to incorporate thematic categories that the focus groups reported as relevant to intensive care unit nurses. Institutions that wish to design a resilience program for intensive care unit nurses to reduce burnout syndrome need an understanding of the barriers and concerns relevant to their local intensive care unit nurses.
*29212643* 29212643 Sleep Disturbances and Fatigue in Critically Ill Patients. AACN Adv Crit Care 2011; 22 (3): 204-24 *21808157* 21808157 A minimal physiologically-based pharmacokinetic model with a nested endosome compartment for novel engineered antibodies. AAPS J 2018; 20 (3): 48
We proposed here a minimal physiologically-based pharmacokinetic (mPBPK) m6odel for a group of novel engineered antibodies in mice and humans. These antibodies are designed with altered binding properties of their Fc domain with neonatal Fc receptor (FcRn) or the Fab domain with their cognate targets (recycling antibodies) in acidic endosomes. To enable simulations of such binding features in the change of antibody pharmacokinetics and its target suppression, we nested an endothelial endosome compartment in parallel with plasma compartment based on our previously established mPBPK model. The fluid-phase pinocytosis rate from plasma to endothelial endosomes was reflected by the clearance of antibodies in FcRn dysfunctional humans or FcRn-knockout mice. The endosomal recycling rate of FcRn-bound antibodies was calculated based on the reported endosomal transit time. The nonspecific catabolism in endosomes was fitted using pharmacokinetic data of a human wide type IgG1 adalimumab in humans and B21M in human FcRn (hFcRn) transgenic mice. The developed model adequately predicted the pharmacokinetics of infliximab, motavizumab, and an Fc variant of motavizumab in humans and the pharmacokinetics of bevacizumab, an Fc variant of bevacizumab, and a recycling antibody PH-IgG1 and its non-pH dependent counterpart NPH-IgG1 in hFcRn transgenic mice. Our proposed model provides a platform for evaluation of the pharmacokinetics and disposition behaviors of Fc-engineered antibodies and recycling antibodies.
*29541870* 29541870 Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein?Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6. AAPS J 2016; 18 (3): 767-76
Disease-mediated therapeutic protein?drug interactions have recently gained attention from regulatory agencies and pharmaceutical industries in the development of new biological products. In this study, we developed a physiologically based pharmacokinetic (PBPK) model using SimCYP to predict the impact of elevated interleukin-6 (IL-6) levels on cytochrome P450 (CYP) enzymes and the treatment effect of an anti-IL-6 monoclonal antibody, sirukumab, in patients with rheumatoid arthritis (RA). A virtual RA patient population was first constructed by incorporating the impact of systemic IL-6 level on hepatic and intestinal expression of multiple CYP enzymes with information from in vitro studies. Then, a PBPK model for CYP enzyme substrates was developed for healthy adult subjects. After incorporating the virtual RA patient population, the PBPK model was applied to quantitatively predict pharmacokinetics of multiple CYP substrates in RA patients before and after sirukumab treatment from a clinical cocktail drug interaction study. The results suggested that, compared with observed clinical data, changes in systemic exposure to multiple CYP substrates by anti-IL-6 treatment in virtual RA patients have been reasonably captured by the PBPK model, as manifested by modulations in area under plasma concentration versus time curves for midazolam, omeprazole, S-warfarin, and caffeine. This PBPK model reasonably captured the modulation effect of IL-6 and sirukumab on activity of CYP3A, CYP2C9, CYP2C19, and CYP1A2 and holds the potential to be utilized to assess the modulation effect of sirukumab on the metabolism and pharmacokinetics of concomitant small-molecule drugs in RA patients.
*26961818* 26961818 Aggregation Kinetics for IgG1-Based Monoclonal Antibody Therapeutics. AAPS J 2016; 18 (3): 689-702
Monoclonal antibodies (mAbs) as a class of therapeutic molecules are finding an increasing demand in the biotechnology industry for the treatment of diseases like cancer and multiple sclerosis. A key challenge associated to successful commercialization of mAbs is that from the various physical and chemical instabilities that are inherent to these molecules. Out of all probable instabilities, aggregation of mAbs has been a major problem that has been associated with a change in the protein structure and is a hurdle in various upstream and downstream processes. It can stimulate immune response causing protein misfolding having deleterious and harmful effects inside a cell. Also, the extra cost incurred to remove aggregated mAbs from the rest of the batch is huge. Size exclusion chromatography (SEC) is a major technique for characterizing aggregation in mAbs where change in the aggregates? size over time is estimated. The current project is an attempt to understand the rate and mechanism of formation of higher order oligomers when subjected to different environmental conditions such as buffer type, temperature, pH, and salt concentration. The results will be useful in avoiding the product exposure to conditions that can induce aggregation during upstream, downstream, and storage process. Extended Lumry-Eyring model (ELE), Lumry-Eyring Native Polymerization model (LENP), and Finke-Watzky model (F-W) have been employed in this work to fit the aggregation experimental data and results are compared to find the best fit model for mAb aggregation to connect the theoretical dots with the reality.
*26902302* 26902302 Pre-existing Antibody: Biotherapeutic Modality-Based Review. AAPS J 2016; 18 (2): 311-20
Pre-existing antibodies to biotherapeutic drugs have been detected in drug-naļve subjects for a variety of biotherapeutic modalities. Pre-existing antibodies are immunoglobulins that are either specific or cross-reacting with a protein or glycan epitopes on a biotherapeutic compound. Although the exact cause for pre-existing antibodies is often unknown, environmental exposures to non-human proteins, glycans, and structurally similar products are frequently proposed as factors. Clinical consequences of the pre-existing antibodies vary from an adverse effect on patient safety to no impact at all and remain highly dependent on the biotherapeutic drug modality and therapeutic indication. As such, pre-existing antibodies are viewed as an immunogenicity risk factor requiring a careful evaluation. Herein, the relationships between biotherapeutic modalities to the nature, prevalence, and clinical consequences of pre-existing antibodies are reviewed. Initial evidence for pre-existing antibody is often identified during anti-drug antibody (ADA) assay development. Other interfering factors known to cause false ADA positive signal, including circulating multimeric drug target, rheumatoid factors, and heterophilic antibodies, are discussed.
*26821802* 26821802 Evaluating and Reporting the Immunogenicity Impacts for Biological Products?a Clinical Pharmacology Perspective. AAPS J 2016; 18 (2): 395-403
Immunogenicity assessment is important for biological products due to potential impacts of immunogenicity on safety and efficacy. We reviewed the prescribing information and the FDA?s clinical pharmacology review of 121 approved biological products for evaluating and reporting of immunogenicity data. Of the 121 products, 89% (n?=?108) reported the incidence of immunogenicity and 49% (n?=?59) reported immunogenicity impact on efficacy. However, only 26% (n?=?31) reported whether the immunogenicity affected pharmacokinetics. A subset of 16 products reported effects of anti-drug antibodies (ADA) on both systemic clearance and efficacy; 8 of 16 products had increased systemic clearance coinciding with reduced efficacy, and 6 of 16 products had no changes in either clearance or efficacy. Factors contributing to infrequent reporting of the ADA effect on exposure and methods for determining the effect of ADA on exposure are summarized. Measuring ADA and drug concentrations concurrently over time enables the evaluation of ADA impact on pharmacokinetics. Within-subject comparison of concentration data (before vs. after ADA formation) is a useful alternative to between-subject (ADA+ vs. ADA?) comparison when sample size is limited or when the majority of subjects developed ADA. The biological complexity of immune responses presents challenges to quantifying the ADA impact on pharmacokinetics using model-based methods. Our findings support that pharmacokinetic exposure is more sensitive than efficacy endpoints for evaluating ADA effects. A decrease in drug concentration due to formation of ADA during treatment can serve as an early indicator for potential reduced efficacy occurring at a later time.
*26721560* 26721560 Pharma Success in Product Development?Does Biotechnology Change the Paradigm in Product Development and Attrition. AAPS J 2016; 18 (1): 281-5
The biotechnology segment of the overall biopharma industry has existed for only about 40?45 years, as a driver of new product development. This driving force was initiated with the FDA approval of recombinant human insulin in 1982, originating from the Genentech company. The pharma industry in the early years of 1970s and 1980s engaged with biotechnology companies only to a small extent with their in-licensing of a few recombinant molecules, led by Roche, Eli Lilly, and Johnson and Johnson. However, subsequently and dramatically over the last 25 years, biotechnology has become a primary driver of product and technology innovation and has become a cornerstone in new product development by all biopharma companies. This review demonstrates these evolutionary changes regarding approved products, product pipelines, novelty of the products, FDA approval rates, product sales, financial R&D investments in biotechnology, partnerships, mergers and acquisitions, and patent issues. We now have about 300 biotechnology products approved in USA covering 16 medical disciplines and about 250 indications, with the engagement of 25 pharma companies, along with their biotechnology company innovators and partners. The biotechnology pipeline involves over 1000 molecules in clinical trials, including over 300 molecules associated with the top 10 pharma companies. Product approval rates by the FDA for biotechnology products are over double the rate for drugs. Yes, the R&D paradigm has changed with biotechnology now as one of the major focuses for new product development with novel molecules by the whole biopharma industry.
*26475480* 26475480 Recommendations for Use and Fit-for-Purpose Validation of Biomarker Multiplex Ligand Binding Assays in Drug Development. AAPS J 2016; 18 (1): 1-14
Multiplex ligand binding assays (LBAs) are increasingly being used to support many stages of drug development. The complexity of multiplex assays creates many unique challenges in comparison to single-plexed assays leading to various adjustments for validation and potentially during sample analysis to accommodate all of the analytes being measured. This often requires a compromise in decision making with respect to choosing final assay conditions and acceptance criteria of some key assay parameters, depending on the intended use of the assay. The critical parameters that are impacted due to the added challenges associated with multiplexing include the minimum required dilution (MRD), quality control samples that span the range of all analytes being measured, quantitative ranges which can be compromised for certain targets, achieving parallelism for all analytes of interest, cross-talk across assays, freeze-thaw stability across analytes, among many others. Thus, these challenges also increase the complexity of validating the performance of the assay for its intended use. This paper describes the challenges encountered with multiplex LBAs, discusses the underlying causes, and provides solutions to help overcome these challenges. Finally, we provide recommendations on how to perform a fit-for-purpose-based validation, emphasizing issues that are unique to multiplex kit assays.
*26377333* 26377333 Evaluation of IgE Antibodies to Omalizumab (Xolair®) and Their Potential Correlation to Anaphylaxis. AAPS J 2016; 18 (1): 115-23
Omalizumab (Xolair®) is a recombinant humanized monoclonal antibody that selectively binds to human immunoglobulin E (IgE). Omalizumab is used to treat IgE-mediated diseases such as chronic idiopathic urticaria (CIU) and moderate to severe allergic asthma. In pre-marketing clinical trials in patients with asthma, anaphylaxis was reported in 3 of 3,507 (0.1%) patients. In post-marketing spontaneous reports, the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2% of patients based on an estimated exposure of about 57,300 patients from June 2003 through December 2006. To better understand the risk of anaphylaxis in patients with allergic asthma receiving omalizumab, a post-marketing pharmacosurveillance study was initiated in 2009. As part of this study, an assay was developed to detect antibodies of IgE isotype to omalizumab. Serum samples from patients in the study were evaluated using this assay. Our results indicated that there was no observable correlation between either anaphylaxis or skin test reactivity and the presence of antibodies of IgE isotype to omalizumab. Here, we discuss the development of this assay as well as the results of the immunogenicity assessment.
*26340860* 26340860 Therapeutic Applications of Curcumin Nanoformulations. AAPS J 2015; 17 (6): 1341-56
Curcumin (diferuloylmethane) is a bioactive and major phenolic component of turmeric derived from the rhizomes of curcuma longa linn. For centuries, curcumin has exhibited excellent therapeutic benefits in various diseases. Owing to its anti-oxidant and anti-inflammatory properties, curcumin plays a significant beneficial and pleiotropic regulatory role in various pathological conditions including cancer, cardiovascular disease, Alzheimer?s disease, inflammatory disorders, neurological disorders, and so on. Despite such phenomenal advances in medicinal applications, the clinical implication of native curcumin is hindered due to low solubility, physico-chemical instability, poor bioavailability, rapid metabolism, and poor pharmacokinetics. However, these issues can be overcome by utilizing an efficient delivery system. Active scientific research was initiated in 2005 to improve curcumin?s pharmacokinetics, systemic bioavailability, and biological activity by encapsulating or by loading curcumin into nanoform(s) (nanoformulations). A significant number of nanoformulations exist that can be translated toward medicinal use upon successful completion of pre-clinical and human clinical trials. Considering this perspective, current review provides an overview of an efficient curcumin nanoformulation for a targeted therapeutic option for various human diseases. In this review article, we discuss the clinical evidence, current status, and future opportunities of curcumin nanoformulation(s) in the field of medicine. In addition, this review presents a concise summary of the actions required to develop curcumin nanoformulations as pharmaceutical or nutraceutical candidates.
*26335307* 26335307 A Modeling and Simulation Framework for Adverse Events in Erlotinib-Treated Non-Small-Cell Lung Cancer Patients. AAPS J 2015; 17 (6): 1483-91
Treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treating non-small-cell lung cancer (NSCLC) and other cancers, is frequently associated with adverse events (AE). We present a modeling and simulation framework for the most common erlotinib-induced AE, rash, and diarrhea, providing insights into erlotinib toxicity. We used the framework to investigate the safety of high-dose erlotinib pulses proposed to limit acquired resistance while treating NSCLC. Continuous-time Markov models were developed using rash and diarrhea AE data from 39 NSCLC patients treated with erlotinib (150 mg/day). Exposure and different covariates were investigated as predictors of variability. Rash was also tested as a survival predictor. Models developed were used in a simulation analysis to compare the toxicities of different regimens, including the previously mentioned pulsed strategy. Probabilities of experiencing rash or diarrhea were found to be highest early during treatment. Rash, but not diarrhea, was positively correlated with erlotinib exposure. In contrast with some common understandings, radiotherapy decreased transitioning to higher rash grades by 81% (p?0.01), and experiencing rash was not correlated with positive survival outcomes. Model simulations predicted that the proposed pulsed regimen (1600 mg/week?+?50 mg/day remaining week days) results in a maximum of 20% of the patients suffering from severe rash throughout the treatment course in comparison to 12% when treated with standard dosing (150 mg/day). In conclusion, the framework demonstrated that radiotherapy attenuates erlotinib-induced rash, providing an opportunity to use radiotherapy and erlotinib together, and demonstrated the tolerability of high-dose pulses intended to address acquired resistance to erlotinib.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-015-9815-8) contains supplementary material, which is available to authorized users.
*26286677* 26286677 Erratum to: Is Extrapolation of the Safety and Efficacy Data in One Indication to Another Appropriate for Biosimilars? AAPS J 2015; 17 (6): 1520-1 *26265095* 26265095 Clinical Immunogenicity of rHuPH20, a Hyaluronidase Enabling Subcutaneous Drug Administration. AAPS J 2015; 17 (5): 1144-56
Recombinant human PH20 hyaluronidase (rHuPH20) is used to facilitate dispersion of subcutaneously delivered fluids and drugs. This report summarizes rHuPH20 immunogenicity findings from clinical trials where rHuPH20 was co-administered with SC human immunoglobulin, trastuzumab, rituximab, or insulin. Plasma samples were obtained from evaluable subjects participating in ten different clinical trials as well as from healthy plasma donors. A bridging immunoassay and a modified hyaluronidase activity assay were used to determine rHuPH20-reactive antibody titers and neutralizing antibodies, respectively. rHuPH20-binding antibody populations from selected subjects with positive titers were affinity-purified and subjected to further characterization such as cross-reactivity with endogenous PH20. Among individual trials, the prevalence of pre-existing rHuPH20-reactive antibodies varied between 3 and 12%, excepting the primary immunodeficiency (PID) studies. Incidence of treatment-induced rHuPH20 antibodies was 2 to 18%, with the highest titers (81,920) observed in PID. No neutralizing antibodies were observed. Within most trials, the kinetics of antibody responses were comparable between pre-existing and treatment-induced antibody responses, although responses classified as persistent were more common in subjects with pre-existing titers. There was no association between antibody positivity and either local or systemic adverse events. Pre-existing and treatment-induced antibody populations were of similar immunoglobulin isotypes and cross-reacted to endogenous PH20 to similar extents. No cross-reactivity to PH20 paralogs was detected. rHuPH20 induces only modest immunogenicity which has no association with adverse events. In addition, antibodies purified from baseline-positive individuals are qualitatively similar to those purified from individuals developing rHuPH20-reactive antibodies following exposure to the enzyme.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-015-9782-0) contains supplementary material, which is available to authorized users.
*25967925* 25967925 A Review of Clinical Translation of Inorganic Nanoparticles. AAPS J 2015; 17 (5): 1041-54
Inorganic nanoparticles are widely used for therapeutic and diagnostic purposes as they offer unique features as compared with their organic and polymeric counterparts. As such, inorganic nanoparticles represent an exciting opportunity to develop drug delivery and imaging systems that are poised to tackle unique challenges which are currently unaddressed in clinical settings. Despite these clear advantages, very few inorganic nanoparticle systems have entered the clinic. Here, we review the current clinical landscape of inorganic nanoparticle systems and their opportunities and challenges, with particular emphasis on gold-, iron-oxide- and silica-based nanoparticle systems. Key examples of inorganic nanoparticles that are currently being investigated in the clinic (e.g., trials which are recruiting or currently active but not completed) are highlighted, along with the preclinical work that these examples have leveraged to transition from the lab to the clinic.
*25956384* 25956384 Development and Fit-for-Purpose Validation of a Soluble Human Programmed Death-1 Protein Assay. AAPS J 2015; 17 (4): 976-87
Programmed death-1 (PD-1) protein is a co-inhibitory receptor which negatively regulates immune cell activation and permits tumors to evade normal immune defense. Anti-PD-1 antibodies have been shown to restore immune cell activation and effector function?an exciting breakthrough in cancer immunotherapy. Recent reports have documented a soluble form of PD-1 (sPD-1) in the circulation of normal and disease state individuals. A clinical assay to quantify sPD-1 would contribute to the understanding of sPD-1-function and facilitate the development of anti-PD-1 drugs. Here, we report the development and validation of a sPD-1 protein assay. The assay validation followed the framework for full validation of a biotherapeutic pharmacokinetic assay. A purified recombinant human PD-1 protein was characterized extensively and was identified as the assay reference material which mimics the endogenous analyte in structure and function. The lower limit of quantitation (LLOQ) was determined to be 100 pg/mL, with a dynamic range spanning three logs to 10,000 pg/mL. The intra- and inter-assay imprecision were ?15%, and the assay bias (percent deviation) was ?10%. Potential matrix effects were investigated in sera from both normal healthy volunteers and selected cancer patients. Bulk-prepared frozen standards and pre-coated Streptavidin plates were used in the assay to ensure consistency in assay performance over time. This assay appears to specifically measure total sPD-1 protein since the human anti-PD-1 antibody, nivolumab, and the endogenous ligands of PD-1 protein, PDL-1 and PDL-2, do not interfere with the assay.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-015-9762-4) contains supplementary material, which is available to authorized users.
*25924887* 25924887 Translational Nano-Medicines: Targeted Therapeutic Delivery for Cancer and Inflammatory Diseases. AAPS J 2015; 17 (4): 813-27
With the advent of novel and personalized therapeutic approaches for cancer and inflammatory diseases, there is a growing demand for designing delivery systems that circumvent some of the limitation with the current therapeutic strategies. Nanoparticle-based delivery of drugs has provided means of overcoming some of these limitations by ensuring the drug payload is directed to the disease site and insuring reduced off-target activity. This review highlights the challenges posed by the solid tumor microenvironment and the systemic limitations for effective chemotherapy. It then assesses the basis of nanoparticle-based targeting to the tumor tissues, which helps to overcome some of the microenvironmental and systemic limitations to therapy. We have extensively focused on some of the tumor multidrug resistance mechanisms (e.g., hypoxia and aerobic glycolysis) that contribute to the development of multidrug resistance and how targeted nano-approaches can be adopted to overcome drug resistance. Finally, we assess the combinatorial approach and how this platform has been used to develop multifunctional delivery systems for cancer therapy. The review article also focuses on inflammatory diseases, the biological therapies available for its treatment, and the concept of macrophage repolarization for the treatment of inflammatory diseases.
*25921939* 25921939 Mesenchymal Stromal/Stem Cell and Minocycline-Loaded Hydrogels Inhibit the Growth of Staphylococcus aureus that Evades Immunomodulation of Blood-Derived Leukocytes. AAPS J 2015; 17 (3): 620-30
Mesenchymal stromal/stem cells (MSCs) have demonstrated favorable wound healing properties in addition to their differentiation capacity. MSCs encapsulated in biomaterials such as gelatin and polyethylene glycol (PEG) composite hydrogels have displayed an immunophenotype change that leads to the release of cytokines and growth factors to accelerate wound healing. However, therapeutic potential of implanted MSC-loaded hydrogels may be limited by non-specific protein adsorption that facilitates adhesion of bacterial pathogens such as planktonic Staphylococcus aureus (SA) to the surface with subsequent biofilm formation resistant to immune cell recognition and antibiotic activity. In this study, we demonstrate that blood-derived primary leukocytes and bone marrow-derived MSCs cannot inhibit colony-forming abilities of planktonic or biofilm-associated SA. However, we show that hydrogels loaded with MSCs and minocycline significantly inhibit colony-forming abilities of planktonic SA while maintaining MSC viability and multipotency. Our results suggest that minocycline and MSC-loaded hydrogels may decrease the bioburden of SA at implant sites in wounds, and may improve the wound healing capabilities of MSC-loaded hydrogels.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-015-9728-6) contains supplementary material, which is available to authorized users.
*25716147* 25716147 Comparison of Nonlinear Mixed Effects Models and Noncompartmental Approaches in Detecting Pharmacogenetic Covariates. AAPS J 2015; 17 (3): 597-608
Genetic data is now collected in many clinical trials, especially in population pharmacokinetic studies. There is no consensus on methods to test the association between pharmacokinetics and genetic covariates. We performed a simulation study inspired by real clinical trials, using the pharmacokinetics (PK) of a compound under development having a nonlinear bioavailability along with genotypes for 176 single nucleotide polymorphisms (SNPs). Scenarios included 78 subjects extensively sampled (16 observations per subject) to simulate a phase I study, or 384 subjects with the same rich design. Under the alternative hypothesis (H1), six SNPs were drawn randomly to affect the log-clearance under an additive linear model. For each scenario, 200 PK data sets were simulated under the null hypothesis (no gene effect) and H1. We compared 16 combinations of four association tests, a stepwise procedure and three penalised regressions (ridge regression, Lasso, HyperLasso), applied to four pharmacokinetic phenotypes, two observed concentrations, area under the curve estimated by noncompartmental analysis and model-based clearance. The different combinations were compared in terms of true and false positives and probability to detect the genetic effects. In presence of nonlinearity and/or variability in bioavailability, model-based phenotype allowed a higher probability to detect the SNPs than other phenotypes. In a realistic setting with a limited number of subjects, all methods showed a low ability to detect genetic effects. Ridge regression had the best probability to detect SNPs, but also a higher number of false positives. No association test showed a much higher power than the others.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-015-9726-8) contains supplementary material, which is available to authorized users.
*25693489* 25693489 Fetal Microchimerism in Cancer Protection and Promotion: Current Understanding in Dogs and the Implications for Human Health. AAPS J 2015; 17 (3): 506-12
Fetal microchimerism is the co-existence of small numbers of cells from genetically distinct individuals living within a mother?s body following pregnancy. During pregnancy, bi-directional exchange of cells occurs resulting in maternal microchimerism and even sibling microchimerism in offspring. The presence of fetal microchimerism has been identified with lower frequency in patients with cancers such as breast and lymphoma and with higher frequency in patients with colon cancer and autoimmune diseases. Microchimeric cells have been identified in healing and healed tissues as well as normal and tumor tissues. This has led to the hypothesis that fetal microchimerism may play a protective role in some cancers and may provoke other cancers or autoimmune disease. The long periods of risk for these diseases make it a challenge to prospectively study this phenomenon in human populations. Dogs get similar cancers as humans, share our homes and environmental exposures, and live compressed life-spans, allowing easier prospective study of disease development. This review describes the current state of understanding of fetal microchimerism in humans and dogs and highlights the similarities of the common cancers mammary carcinoma, lymphoma, and colon cancer between the two species. Study of fetal microchimerism in dogs might hold the key to characterization of the type and function of microchimeric cells and their role in health and disease. Such an understanding could then be applied to preventing and treating disease in humans.
*25693490* 25693490 Harnessing Biomaterials to Engineer the Lymph Node Microenvironment for Immunity or Tolerance. AAPS J 2015; 17 (2): 323-38
Nanoparticles, microparticles, and other biomaterials are advantageous in vaccination because these materials provide opportunities to modulate specific characteristics of immune responses. This idea of ?tuning? immune responses has recently been used to combat infectious diseases and cancer, and to induce tolerance during organ transplants or autoimmune disease. Lymph nodes and other secondary lymphoid organs such as the spleen play crucial roles in determining if and how these responses develop following vaccination or immunotherapy. Thus, by manipulating the local microenvironments within these immunological command centers, the nature of systemic immune response can be controlled. This review provides recent examples that harness the interactions between biomaterials and lymph nodes or other secondary lymphoid organs to generate immunity or promote tolerance. These strategies draw on mechanical properties, surface chemistry, stability, and targeting to alter the interactions of cells, signals, and vaccine components in lymph nodes. While there are still many unanswered questions surrounding how best to design biomaterial-based vaccines to promote specific structures or functions in lymph nodes, features such as controlled release and targeting will help pave the way for the next generation of vaccines and immunotherapies that generate immune responses tuned for specific applications.
*25533221* 25533221 Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition. AAPS J 2015; 17 (2): 389-99
Prediction of human pharmacokinetics (PK) can be challenging for monoclonal antibodies (mAbs) exhibiting target-mediated drug disposition (TMDD). In this study, we performed a quantitative analysis of a diverse set of six mAbs exhibiting TMDD to explore translational rules that can be utilized to predict human PK. A TMDD model with rapid-binding approximation was utilized to fit PK and PD (i.e., free and/or total target levels) data, and average absolute fold error (AAFE) was calculated for each model parameter. Based on the comparative analysis, translational rules were developed and applied to a test antibody not included in the original analysis. AAFE of less than two-fold was observed between monkey and human for baseline target levels (R0), body-weight (BW) normalized central elimination rate (Kel/BW?0.25) and central volume (Vc/BW1.0). AAFE of less than three-fold was estimated for the binding affinity constant (KD). The other four parameters, i.e., complex turnover rate (Kint), target turnover rate (Kdeg), central to peripheral distribution rate constant (Kpt) and peripheral to central rate constant (Ktp) were poorly correlated between monkey and human. The projected human PK of test antibody based on the translation rules was in good agreement with the observed nonlinear PK. In conclusion, we recommend a TMDD model-based prediction approach that integrates in vitro human biomeasures and in vivo preclinical data using translation rules developed in this study.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-014-9690-8) contains supplementary material, which is available to authorized users.
*25445845* 25445845 Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality. AAPS J 2015; 17 (1): 35-43
Immunogenicity (the development of an adaptive immune response reactive with a therapeutic) is a well-described but unwanted facet of biotherapeutic development. There are commonly applied procedures for immunogenicity risk assessment, testing strategies, and bioanalysis. With some modifications, these can be applied to new biotherapeutic modalities. For novel therapies such as antibody-drug conjugates (ADCs), the unique structural components may contribute additional complexities to both immunologic responses and bioanalytical methods. US product inserts (USPIs) for two commercially available ADCs detail the incidence of immunogenicity; however, the body of literature on immunogenicity of ADCs is limited. We recently participated in a conference session on this topic (Annual meeting of the American Association of Pharmaceutical Scientists, held November 2013 in San Antonio, TX, USA. The meeting featured the Symposium: Immunogenicity Assessment for Novel Antibody Drug Conjugates, Nonclinical to Clinical) which prompted an effort to share our perspectives on how immunogenicity risk assessment, testing strategies, and bioanalytical methods can be adapted to reflect the complexity of ADC therapeutics.
*25380723* 25380723 Early Engineering Approaches to Improve Peptide Developability and Manufacturability. AAPS J 2015; 17 (1): 111-20
Downstream success in Pharmaceutical Development requires thoughtful molecule design early in the lifetime of any potential therapeutic. Most therapeutic monoclonal antibodies are quite similar with respect to their developability properties. However, the properties of therapeutic peptides tend to be as diverse as the molecules themselves. Analysis of the primary sequence reveals sites of potential adverse posttranslational modifications including asparagine deamidation, aspartic acid isomerization, methionine, tryptophan, and cysteine oxidation and, potentially, chemical and proteolytic degradation liabilities that can impact the developability and manufacturability of a potential therapeutic peptide. Assessing these liabilities, both biophysically and functionally, early in a molecule?s lifetime can drive a more effective path forward in the drug discovery process. In addition to these potential liabilities, more complex peptides that contain multiple disulfide bonds can pose particular challenges with respect to production and manufacturability. Approaches to reducing the disulfide bond complexity of these peptides are often explored with mixed success. Proteolytic degradation is a major contributor to decreased half-life and efficacy. Addressing this aspect of peptide stability early in the discovery process increases downstream success. We will address aspects of peptide sequence analysis, molecule complexity, developability analysis, and manufacturing routes that drive the decision making processes during peptide therapeutic development.
*25338742* 25338742 Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis. AAPS J 2014; 16 (6): 1204-13
Autoimmune diseases such as multiple sclerosis (MS) are characterized by the breakdown of immune tolerance to autoantigens. Targeting surface receptors on immune cells offers a unique strategy for reprogramming immune responses in autoimmune diseases. The B7 signaling pathway was targeted using adaptations of soluble antigen array (SAgA) technology achieved by covalently linking B7-binding peptides and disease causing autoantigen (proteolipid peptide (PLP)) to hyaluronic acid (HA). We hypothesized that co-delivery of a B7-binding peptide and autoantigen would suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Three independent B7-targeted SAgAs were created containing peptides to either inhibit or potentially stimulate the B7 signaling pathway. Surprisingly, all SAgAs were found to suppress EAE disease symptoms. Altered cytokine expression was observed in primary splenocytes isolated from SAgA-treated mice, indicating that SAgAs with different B7-binding peptides may suppress EAE through different immunological mechanisms. This antigen-specific immunotherapy using SAgAs can successfully suppress EAE through co-delivery of autoantigen and peptides targeting with the B7 signaling pathway.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-014-9671-y) contains supplementary material, which is available to authorized users.
*25297853* 25297853 Next Generation Ligand Binding Assays?Review of Emerging Technologies? Capabilities to Enhance Throughput and Multiplexing. AAPS J 2014; 16 (6): 1175-84
The purpose of this manuscript is to provide a summary of the evaluation done by the Throughput and Multiplexing subteam on five emerging technologies: Single molecule array (Simoa?), Optimiser?, CyTOF® (Mass cytometry), SQIDLite?, and iLite?. Most of the information is presented with a minimum amount of published data and much is based on discussions with users and the vendor, to help provide the reader with an unbiased assessment of where the subteam sees each technology fitting best in the bioanalysis of large molecules. The evaluation focuses on technologies with advantages in throughput and multiplexing, but is wide enough to capture their strengths in other areas. While all platforms may be suited to support bioanalysis in the discovery space, because of their emergent nature, only Optimiser and SQIDLite are currently ready to be used in the regulated space. With the exception of Optimiser, each instrument/technology requires an up-front investment from the bioanalytical lab that will need justification during capital budget discussions. Ultimately, the platform choice should be driven by the quality of data, project needs, and the intended use of the data generated. In a time- and resource-constrained environment, it is not possible to evaluate all emergent technologies available in the market; we hope that this review gives the reader some of the information needed to decide which technology he/she may want to consider evaluating to support their drug development program in comparison to the options they already have in their hands.
*25193269* 25193269 Simulation of Monoclonal Antibody Pharmacokinetics in HumansUsing a Minimal Physiologically Based Model. AAPS J 2014; 16 (5): 1097-109
Compared to small chemical molecules, monoclonal antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behaviour characterised by relatively poor cellular permeability, minimal renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A minimal physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics of mAbs in humans was developed. Within the model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The tissue compartment is further sub-divided into vascular, endothelial and interstitial spaces. The model simultaneously describes the levels of endogenous IgG and exogenous mAbs in each compartment and sub-compartment and, in particular, considers the competition of these two species for FcRn binding in the endothelial space. A Monte-Carlo sampling approach is used to simulate the concentrations of endogenous IgG and mAb in a human population. Existing targeted-mediated drug disposition (TMDD) models are coupled with the minimal PBPK model to provide a general platform for simulating the pharmacokinetics of therapeutic antibodies using primarily pre-clinical data inputs. The feasibility of utilising pre-clinical data to parameterise the model and to simulate the pharmacokinetics of adalimumab and an anti-ALK1 antibody (PF-03446962) in a population of individuals was investigated and results were compared to published clinical data.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-014-9640-5) contains supplementary material, which is available to authorized users.
*25004823* 25004823 Biological Products for the Treatment of Psoriasis: Therapeutic Targets, Pharmacodynamics and Disease-Drug-Drug Interaction Implications. AAPS J 2014; 16 (5): 938-47
Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocytes. Currently approved biological products for psoriasis treatment fall into two main classes: cytokine modulators and biologics targeting T cells. In psoriatic patients, elevated levels of proinflammatory cytokines are observed. Elevated proinflammatory cytokines can suppress some cytochrome P450 (CYP) enzymes, and the treatment of psoriasis with biological products can reduce proinflammatory cytokine levels. Therefore, the exposure of CYP substrate drugs is anticipated to be affected by the psoriasis disease resulting in a higher exposure than in healthy state (named disease-drug interaction) as well as by the biological treatments due to disease improvements resulting in a decrease in exposure (named disease-drug-drug interaction, disease-DDI). However, the quantitative impact on CYP substrate exposure due to disease or due to treatment with biological products remains to be evaluated. The objective of the current review is to provide an overview of the therapeutic targets and cytokine-related pharmacodynamic effects of biological products in psoriasis treatment with a particular focus on their implications for disease-DDI. The clinical study design considerations for psoriasis disease-DDI evaluation are also discussed.
*24993574* 24993574 Induction of Death Receptor CD95 and Co-stimulatory Molecules CD80 and CD86 by Meningococcal Capsular Polysaccharide-Loaded Vaccine Nanoparticles. AAPS J 2014; 16 (5): 986-93
Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis, and its capsular polysaccharides (CPS) are a major virulence factor in meningococcal infections and form the basis for serogroup designation and protective vaccines. We formulated a novel nanovaccine containing meningococcal CPS as an antigen encapsulated in albumin-based nanoparticles (NPs) that does not require chemical conjugation to a protein carrier. These nanoparticles are taken up by antigen-presenting cells and act as antigen depot by slowly releasing the antigen. In this study, we determined the ability of CPS-loaded vaccine nanoparticles to induce co-stimulatory molecules, namely CD80, CD86, and CD95 that impact effective antigen presentation. Co-stimulatory molecule gene induction and surface expression on macrophages and dendritic cells pulsed with meningococcal CPS-loaded nanoparticles were investigated using gene array and flow cytometry methods. Meningococcal CPS-loaded NP significantly induced the surface protein expression of CD80 and CD86, markers of dendritic cell maturation, in human THP-1 macrophages and in murine dendritic cells DC2.4 in a dose-dependent manner. The massive upregulation was also observed at the gene expression. However, high dose of CPS-loaded NP, but not empty NP, induced the expression of death receptor CD95 (Fas) leading to reduced TNF-? release and reduction in cell viability. The data suggest that high expression of CD95 may lead to death of antigen-presenting cells and consequently suboptimal immune responses to vaccine. The CPS-loaded NP induces the expression of co-stimulatory molecules and acts as antigen depot and can spare antigen dose, highly desirable criteria for vaccine formulations.
*24981893* 24981893 Dashboard Systems: Implementing Pharmacometrics from Bench to Bedside. AAPS J 2014; 16 (5): 925-37
In recent years, there has been increasing interest in the development of medical decision-support tools, including dashboard systems. Dashboard systems are software packages that integrate information and calculations about therapeutics from multiple components into a single interface for use in the clinical environment. Given the high cost of medical care, and the increasing need to demonstrate positive clinical outcomes for reimbursement, dashboard systems may become an important tool for improving patient outcome, improving clinical efficiency and containing healthcare costs. Similarly the costs associated with drug development are also rising. The use of model-based drug development (MBDD) has been proposed as a tool to streamline this process, facilitating the selection of appropriate doses and making informed go/no-go decisions. However, complete implementation of MBDD has not always been successful owing to a variety of factors, including the resources required to provide timely modeling and simulation updates. The application of dashboard systems in drug development reduces the resource requirement and may expedite updating models as new data are collected, allowing modeling results to be available in a timely fashion. In this paper, we present some background information on dashboard systems and propose the use of these systems both in the clinic and during drug development.
*24947898* 24947898 Population Pharmacokinetic Modeling of LY2189102 after Multiple Intravenous and Subcutaneous Administrations. AAPS J 2014; 16 (5): 1009-17
Interleukin-1 beta (IL-1?) is an inflammatory mediator which may contribute to the pathophysiology of rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). Population pharmacokinetics (PK) of LY2189102, a high affinity anti-IL-1? humanized monoclonal immunoglobulin G4 evaluated for efficacy in RA and T2DM, were characterized using data from 79 T2DM subjects (Study H9C-MC-BBDK) who received 13 weekly subcutaneous (SC) doses of LY2189102 (0.6, 18, and 180 mg) and 96 RA subjects (Study H9C-MC-BBDE) who received five weekly intravenous (IV) doses (0.02?2.5 mg/kg). Frequency of anti-drug antibody (ADA) development appears dose-dependent and is different between studies (36.7% in Study H9C-MC-BBDK vs. 2.1% in Study H9C-MC-BBDE), likely due to several factors, including differences in patient population and background medications, administration routes, and assays. A two-compartment model with dose-dependent bioavailability best characterizes LY2189102 PK following IV and SC administration. Typical elimination and distribution clearances, central and peripheral volumes of distribution are 0.222 L/day, 0.518 L/day, 3.08 L, and 1.94 L, resulting in a terminal half-life of 16.8 days. Elimination clearance increased linearly, yet modestly, with baseline creatinine clearance and appears 37.6% higher in subjects who developed ADA. Bioavailability (0.432?0.721) and absorption half-life (94.3?157 h) after SC administration are smaller with larger doses. Overall, LY2189102 PK is consistent with other therapeutic humanized monoclonal antibodies and is likely to support convenient SC dosing.
*24912797* 24912797 Diurnal Variation in P-glycoprotein-Mediated Transport and Cerebrospinal Fluid Turnover in the Brain. AAPS J 2014; 16 (5): 1029-37
Nearly all bodily processes exhibit circadian rhythmicity. As a consequence, the pharmacokinetic and pharmacodynamic properties of a drug may also vary with time of day. The objective of this study was to investigate diurnal variation in processes that regulate drug concentrations in the brain, focusing on P-glycoprotein (P-gp). This efflux transporter limits the distribution of many drugs in the brain. To this end, the exposure to the P-gp substrate quinidine was determined in the plasma and brain tissue after intravenous administration in rats at six different time points over the 24-h period. Our results indicate that time of administration significantly affects the exposure to quinidine in the brain. Upon inhibition of P-gp, exposure to quinidine in brain tissue is constant over the 24-h period. To gain more insight into processes regulating brain concentrations, we used intracerebral microdialysis to determine the concentration of quinidine in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) after intravenous administration at two different time points. The data were analyzed by physiologically based pharmacokinetic modeling using NONMEM. The model shows that the variation is due to higher activity of P-gp-mediated transport from the deep brain compartment to the plasma compartment during the active period. Furthermore, the analysis reveals that CSF flux is higher in the resting period compared to the active period. In conclusion, we show that the exposure to a P-gp substrate in the brain depends on time of administration, thereby providing a new strategy for drug targeting to the brain.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-014-9625-4) contains supplementary material, which is available to authorized users.
*24917180* 24917180 Assessment and Reporting of the Clinical Immunogenicity of Therapeutic Proteins and Peptides?Harmonized Terminology and Tactical Recommendations. AAPS J 2014; 16 (4): 658-73
Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity.
*24764037* 24764037 A White Paper?Consensus and Recommendations of a Global Harmonization Team on Assessing the Impact of Immunogenicity on Pharmacokinetic Measurements. AAPS J 2014; 16 (3): 488-98
The Global Bioanalysis Consortium (GBC) set up an international team to explore the impact of immunogenicity on pharmacokinetic (PK) assessments. The intent of this paper is to define the field and propose best practices when developing PK assays for biotherapeutics. We focus on the impact of anti-drug antibodies (ADA) on the performance of PK assay leading to the impact on the reported drug concentration and exposure. The manuscript describes strategies to assess whether the observed change in the drug concentration is due to the ADA impact on drug clearance rates or is a consequence of ADA interference in the bioanalytical method applied to measure drug concentration. This paper provides the bioanalytical scientist guidance for developing ADA-tolerant PK methods. It is essential that the data generated in the PK, ADA, pharmacodynamic and efficacy/toxicity evaluations are viewed together. Therefore, the extent for the investigation of the PK sensitivity to the presence of ADA should be driven by the project needs and risk based.
*24682765* 24682765 A Network Modeling Approach for the Spatial Distribution and Structure of Bone Mineral Content. AAPS J 2014; 16 (3): 478-87
This study aims to develop a spatial model of bone for quantitative assessments of bone mineral density and microarchitecture. A spatially structured network model for bone microarchitecture was systematically investigated. Bone mineral-forming foci were distributed radially according to the cumulative normal distribution, and Voronoi tessellation was used to obtain edges representing bone mineral lattice. Methods to simulate X-ray images were developed. The network model recapitulated key features of real bone and contained spongy interior regions resembling trabecular bone that transitioned seamlessly to densely mineralized, compact cortical bone-like microarchitecture. Model-simulated imaging profiles were similar to patients? X-ray images. The morphometric metrics were concordant with microcomputed tomography results for real bone. Simulations comparing normal and diseased bone of 20?30 to 70?80 year-olds demonstrated the method?s effectiveness for modeling osteoporosis. The novel spatial model may be useful for pharmacodynamic simulations of bone drugs and for modeling imaging data in clinical trials.
*24671611* 24671611 Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects. AAPS J 2014; 16 (2): 206-13
To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased Cmax (25%???64%), increased area under the plasma level-time curves (30?76%), increased area under the time infinity (43%???80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.
*24357089* 24357089 Mechanistic Pharmacokinetic/Target Engagement/Pharmacodynamic (PK/TE/PD) Modeling in Deciphering Interplay Between a Monoclonal Antibody and Its Soluble Target in Cynomolgus Monkeys. AAPS J 2014; 16 (1): 129-39
For therapeutic monoclonal antibodies (mAbs) against soluble ligands, the free ligand level can, theoretically, be used as a surrogate for efficacy. However, it can be extremely challenging technically to measure free ligand level in the presence of an excessive amount of antibody?ligand complex. The interplay among such mAbs, ligands, and the downstream pharmacodynamic (PD) effects has not been well defined. Using siltuximab and interleukin-6 (IL-6) as model compounds, a pharmacokinetic (PK)/target engagement (TE) model was established via simultaneous fitting of total siltuximab, total IL-6, and free IL-6 concentration profiles following a low dose of siltuximab in cynomolgus monkeys. The model adequately captured the observed data and provided estimation of model parameters with good precision. The PK/TE model was used to predict free IL-6 profiles at higher siltuximab doses, where the accurate determination of free IL-6 concentration became technically too difficult. The measured free IL-6 levels from the low-dose groups and PK/TE model-predicted free IL-6 levels from the high-dose groups were used to drive an indirect response TE/PD model to describe the concentration?effect relationship between free IL-6 and C-reactive protein (CRP). The TE/PD model adequately captured both CRP elevation and CRP suppression in response to free IL-6 concentration change from baseline with a linear stimulation function, providing direct evidence that the PK/TE model-predicted free IL-6 levels from the high-dose groups were accurate. Overall, the results provided an integrated PK/TE/PD modeling and bioanalytical framework for prediction of efficacious dose levels and duration of action for mAbs against soluble ligands with rapid turnover.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-013-9545-8) contains supplementary material, which is available to authorized users.
*24287601* 24287601 Large Molecule Specific Assay Operation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team. AAPS J 2014; 16 (1): 83-8
The L2 Global Harmonization Team on large molecule specific assay operation for protein bioanalysis in support of pharmacokinetics focused on the following topics: setting up a balanced validation design, specificity testing, selectivity testing, dilutional linearity, hook effect, parallelism, and testing of robustness and ruggedness. The team additionally considered the impact of lipemia, hemolysis, and the presence of endogenous analyte on selectivity assessments as well as the occurrence of hook effect in study samples when no hook effect had been observed during pre-study validation.
*24242296* 24242296 Is Extrapolation of the Safety and Efficacy Data in One Indication to Another Appropriate for Biosimilars? AAPS J 2014; 16 (1): 22-6
CT-P13, the world?s first biosimilar monoclonal antibody to infliximab, was approved for marketing in South Korea for all the six indications of infliximab, which Europe may follow, although the product was tested only in rheumatoid arthritis (RA) with a limited pharmacokinetic comparison in ankylosing spondylitis. However, the extrapolation of the efficacy and safety findings of CT-P13 in RA to the other indications appears scientifically challenging when assessed by the current regulatory requirements. RA is not a sensitive clinical model to detect potential differences between CT-P13 and infliximab, and other mechanisms of action than antagonizing tumor necrosis factor ? appear to be also important, which could be different by the approved indications. Furthermore, the immunogenicity and safety profiles of CT-P13 were not sufficiently characterized in that immunogenicity potential was lowest in RA, which was even further suppressed by the concomitant use of methotrexate. Extrapolation of the safety and efficacy data in one indication to another may be inappropriate for biosimilars unless backed up by strong scientific justification, which may include the mechanistic exposure?relationship approach. Therefore, regulatory agencies need to exercise caution before granting extrapolated indications to biosimilars.
*24114449* 24114449 A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation. AAPS J 2013; 15 (4): 1189-99
The SNP A6986G of the CYP3A5 gene (3) results in a non-functional protein due to a splicing defect whereas the C3435T was associated with variable expression of the ABCB1 gene, due to protein instability. Part of the large interindividual variability in tacrolimus efficacy and toxicity can be accounted for by these genetic factors. Seventy-two individuals were examined for A6986G and C3435T polymorphism using a PCR-RFLP-based technique to estimate genotype and allele frequencies in the Jordanian population. The association of age, hematocrit, platelet count, CYP3A5, and ABCB1 polymorphisms with tacrolimus dose- and body-weight-normalized levels in the subset of 38 pediatric renal transplant patients was evaluated. A Markov model was used to evaluate the time-dependent probability of an adverse event occurrence by CYP3A5 phenotypes and ABCB1 genotypes. The time-dependent probability of adverse event was about double in CYP3A5 non-expressors compared to the expressors for the first 12 months of therapy. The CYP3A5 non-expressors had higher corresponding normalized tacrolimus levels compared to the expressors in the first 3 months. The correlation trend between probability of adverse events and normalized tacrolimus concentrations for the two CYP3A5 phenotypes persisted for the first 9 months of therapy. The differences among ABCB1 genotypes in terms of adverse events and normalized tacrolimus levels were only observed in the first 3 months of therapy. The information on CYP3A5 genotypes and tacrolimus dose requirement is important in designing effective programs toward management of tacrolimus side effects particularly for the initial dose when tacrolimus blood levels are not available for therapeutic drug monitoring.
*23990505* 23990505 Epigenetic Cancer Prevention Mechanisms in Skin Cancer. AAPS J 2013; 15 (4): 1064-71
Epigenetics is an important emerging area for study of mechanisms of cancer prevention. In recent years, it has been realized that cancer prevention agents, derived from natural dietary sources, impact cancer cell survival by modulating epigenetic processes. In the present manuscript, we review key epigenetic regulatory mechanisms and examine the impact of sulforaphane and green tea polyphenols on these processes. We also discuss available information on the epigenetics in the context of skin cancer. These studies indicate that diet-derived chemopreventive agents modulate DNA methylation status and histone modification via multiple processes and point to additional areas for study of epigenetic mechanisms in skin cancer.
*23904153* 23904153 Immunogenicity of Subcutaneously Administered Therapeutic Proteins?a Mechanistic Perspective. AAPS J 2013; 15 (4): 897-900
The administration of therapeutic proteins via the subcutaneous route (sc) is desired for compliance and convenience, but could be challenging due to perceived immunogenic potential or unwanted immune responses. There are clinical and preclinical data supporting as well as refuting the generalized notion that sc is more immunogenic. We provide a mechanistic perspective of immunogenicity of therapeutic proteins administered via the sc route and discuss strategies and opportunities for novel therapeutic approaches to mitigate immunogenicity.
*23856740* 23856740 Therapeutic Protein Drug?Drug Interactions: Navigating the Knowledge Gaps?Highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop. AAPS J 2013; 15 (4): 933-40
The investigation of therapeutic protein drug?drug interactions has proven to be challenging. In May 2012, a roundtable was held at the American Association of Pharmaceutical Scientists National Biotechnology Conference to discuss the challenges of preclinical assessment and in vitro to in vivo extrapolation of these interactions. Several weeks later, a 2-day workshop co-sponsored by the U.S. Food and Drug Administration and the International Consortium for Innovation and Quality in Pharmaceutical Development was held to facilitate better understanding of the current science, investigative approaches and knowledge gaps in this field. Both meetings focused primarily on drug interactions involving therapeutic proteins that are pro-inflammatory cytokines or cytokine modulators. In this meeting synopsis, we provide highlights from both meetings and summarize observations and recommendations that were developed to reflect the current state of the art thinking, including a four-step risk assessment that could be used to determine the need (or not) for a dedicated clinical pharmacokinetic interaction study.
*23794076* 23794076 Evaluation of Pre-existing Antibody Presence as a Risk Factor for Posttreatment Anti-drug Antibody Induction: Analysis of Human Clinical Study Data for Multiple Biotherapeutics. AAPS J 2013; 15 (3): 893-6
Biotherapeutic-reactive antibodies in treatment-naļve subjects (i.e., pre-existing antibodies) have been commonly detected during clinical immunogenicity assessments; however information on pre-existing antibody prevalence, physiological effects, and impact on posttreatment anti-drug antibody (ADA) induction remains limited. In this analysis, pre-existing antibody prevalence and impact on posttreatment ADA induction were determined using ADA data from 12 biotherapeutics analyzed in 32 clinical studies. Approximately half (58%) of the biotherapeutics were associated with some level of pre-existing antibodies and 67% of those were associated with posttreatment ADA induction. Across all studies, 5.6% of study subjects demonstrated presence of pre-existing antibodies, among which, 17% of the individual subjects had posttreatment increases in their ADA titers while 16% had decreased titers and 67% had no change in titers. However, in studies conducted in the rheumatoid arthritis (RA) population, 14.8% of RA patients were associated with pre-existing antibodies and 30% of those had posttreatment titer increases. The results suggest that in most study subjects, pre-existing antibodies pose a low risk for posttreatment ADA induction. That said, the high risk of induction implicated for RA patients, primarily observed in treatments evaluating novel antibody-based constructs, indicates that further understanding of the contribution of product and disease-specific factors is needed. Cross-industry efforts to collect and analyze a larger data set would enhance understanding of the prevalence, nature, and physiological consequences of pre-existing antibodies, better inform the immunogenicity risk profiles of products associated with these antibodies and lead to better fit-for-purpose immunogenicity management and mitigation strategies.
*23761225* 23761225 Factors Influencing Magnitude and Duration of Target Inhibition Following Antibody Therapy: Implications in Drug Discovery and Development. AAPS J 2013; 15 (3): 717-27
Antibodies or antibody-related fusion proteins binding to soluble antigens in plasma form an important subclass of approved therapeutics. Pharmaceutical companies are constantly trying to accelerate the pace of drug discovery and development of these antibodies and identify superior candidates in face of significant attrition rates. Understanding the interplay between drug- and target-related factors on magnitude and duration of target inhibition is imperative for successful advancement of these therapeutics. Simulations using a target-mediated drug disposition model were performed to evaluate the influence of antibody-target binding affinity, baseline target concentration, and target turnover on magnitude and duration of soluble target inhibition. These simulations assumed intravenous dosing of the antibody and evaluated multiple parameters over a wide range. These simulations reveal that improvement in affinity reaches a point of diminishing returns following which further improvement in affinity does not alter the magnitude and more importantly the duration of target inhibition. Evaluation of unbound antibody and target kinetics indicated that point of diminishing returns in duration of inhibition was due to target-mediated binding and subsequent elimination of antibody at later time points. Similarly, influence of baseline target concentration and target turnover on magnitude and duration of target inhibition in plasma is shown. Additionally, the fraction of dose eliminated via target mediated elimination (Fel?) can be a useful tool to enable selection of strategies to increase duration of target inhibition. The implications of these simulations in drug discovery and development with regard to target identification, antibody optimization, and backup candidate selection are discussed.
*23588584* 23588584 Theoretical Considerations and Practical Approaches to Address the Effect of Anti-drug Antibody (ADA) on Quantification of Biotherapeutics in Circulation. AAPS J 2013; 15 (3): 646-58
Continuous improvement in bioanalytical method development is desired in order to ensure the quality of the data and to better support pharmacokinetic (PK) and safety studies of biotherapeutics. One area that has been getting increasing attention recently is in the assessment of ?free? and ?total? analyte and the impact of the assay format on those assessments. To compliment these considerations, the authors provide a critical review of available literature and prospectively explore methods to mitigate the potential impact of anti-drug antibody on PK assay measurement. This challenge is of particular interest and importance since biotherapeutic drugs often elicit an immune response, and thus may have a direct impact on quantification of the drug for its PK and safety evaluations.
*23543601* 23543601 The Challenges of Assessing Osteoarthritis and Postoperative Pain in Dogs. AAPS J 2013; 15 (2): 598-607
The challenge of measuring pain in veterinary medicine is compounded by the lack of fully validated, reliable methods to measure and assess pain in nonverbal patients. In human medicine, there are numerous, validated pain assessment tools (PATs) for assessing various, specific types of pain. The advances in human medicine pain management and numerous validated pain scales should serve as incentives and templates to facilitate similar advances in the development of validated PATs for use in dogs (and other species). The limited number of canine PATs constrains our ability to adequately and reliably assess pain. Improving the ability to quantify osteoarthritis and postoperative pain in dogs would enhance the development of analgesics for animals, advance the management of animal pain, facilitate the use of animal pain models in preclinical trials for human analgesics, and provide insight into the quantification of pain responses in humans who lack the ability to adequately communicate. This review describes the need for practical, valid, and reliable PATs for use in veterinary patients and discusses some currently available PATs commonly used to evaluate acute and chronic pain in dogs.
*23456420* 23456420 Population-Based Efficacy Modeling of Omalizumab in Patients with Severe Allergic Asthma Inadequately Controlled with Standard Therapy. AAPS J 2013; 15 (2): 559-70
Omalizumab, a recombinant humanized monoclonal antibody, is the first approved anti-immunoglobulin E (IgE) agent for the treatment of subjects with moderate to severe persistent allergic asthma that are inadequately controlled by the standard of care. The objective of this study was to quantitatively characterize relationships between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) as well as serum free IgE and airway inflammation (as measured by fractional exhaled nitric oxide [FeNO]) using population-based efficacy models. Data were collected from patients in the EXTRA trial who received omalizumab or placebo 150 to 375 mg subcutaneously every 2 or 4 weeks from week 0 to 48 with constant standard of care as background therapy. None of the covariates evaluated, including demographics, disease status, and baseline pharmacodynamic biomarkers, were significant in explaining the variability in the FEV1 or FeNO response to omalizumab. Results from the efficacy models further confirmed the current omalizumab dosing rationale based on the mean target free IgE level of 25 ng/ml and quantified the variability for the target. In addition, the resulting population models could be used to predict population FEV1 or FeNO response for omalizumab and/or other anti-IgE therapeutics for which PK-IgE models are constructed.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-013-9463-9) contains supplementary material, which is available to authorized users.
*23413101* 23413101 Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies. AAPS J 2013; 15 (2): 551-8
The industry-wide biopharmaceutical (i.e., biologic, biotherapeutic) pipeline has been growing at an astonishing rate over the last decade with the proportion of approved new biological entities to new chemical entities on the rise. As biopharmaceuticals appear to be growing in complexity in terms of their structure and mechanism of action, so are interpretation, analysis, and prediction of their quantitative pharmacology. We present here a modeling and simulation (M&S) framework for the successful preclinical development of monoclonal antibodies (as an illustrative example of biopharmaceuticals) and discuss M&S strategies for its implementation. Critical activities during early discovery, lead optimization, and the selection of starting doses for the first-in-human study are discussed in the context of pharmacokinetic?pharmacodynamic (PKPD) and M&S. It was shown that these stages of preclinical development are and should be reliant on M&S activities including systems biology (SB), systems pharmacology (SP), and translational pharmacology (TP). SB, SP, and TP provide an integrated and rationalized framework for decision making during the preclinical development phase. In addition, they provide increased target and systems understanding, describe and interpret data generated in vitro and in vivo, predict human PKPD, and provide a rationalized approach to designing the first-in-human study.
*23408094* 23408094 Dose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches. AAPS J 2013; 15 (2): 377-87
Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration?time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.
*23269526* 23269526 Controlled Release of Simvastatin from In situ Forming Hydrogel Triggers Bone Formation in MC3T3-E1 Cells. AAPS J 2013; 15 (2): 367-76
Simvastatin (SIM), a drug commonly administered for the treatment of hypercholesterolemia, has been recently reported to induce bone regeneration/formation. In this study, we investigated the properties of hydrogel composed of gelatin?poly(ethylene glycol)?tyramine (GPT) as an efficient SIM delivery vehicle that can trigger osteogenic differentiation. Sustained delivery of SIM was achieved through its encapsulation in an injectable, biodegradable GPT-hydrogel. Cross-linking of the gelatin-based GPT-hydrogel was induced by the reaction of horse radish peroxidase and H2O2. GPT-hydrogels of three different matrix stiffness, 1,800 (GPT-hydrogel1), 5,800 (GPT-hydrogel2), and 8,400 Pa (GPT-hydrogel3) were used. The gelation/degradation time and SIM release profiles of hydrogels loaded with two different concentrations of SIM, 1 and 3 mg/ml, were also evaluated. Maximum swelling times of GPT-hydrogel1, GPT-hydrogel2, and GPT-hydrogel3 were observed to be 6, 12, and 20 days, respectively. All GPT-hydrogels showed complete degradation within 55 days. The in vitro SIM release profiles, investigated in PBS buffer (pH 7.4) at 37°C, exhibited typical biphasic release patterns with the initial burst being more rapid with GPT-hydrogel1 compared with GPT-hydrogel3. Substantial increase in matrix metalloproteinase-13, osteocalcin expression levels, and mineralization were seen in osteogenic differentiation system using MC3T3-E1 cells cultured with GPT-hydrogels loaded with SIM in a dose-dependent manner. This study demonstrated that controlled release of SIM from a biodegradable, injectable GPT-hydrogel had a promising role for long-term treatment of chronic degenerative diseases such as disc degenerative disease.
*23250670* 23250670 The Utility of Modeling and Simulation Approaches to Evaluate Immunogenicity Effect on the Therapeutic Protein Pharmacokinetics. AAPS J 2013; 15 (1): 172-82
While therapeutic proteins (TP), particularly recombinant human proteins and fully human monoclonal antibodies, are designed to have a low immunogenic potential in humans, a clinical immune response does sometimes occur and cannot be predicted from preclinical studies. Changes in TP pharmacokinetics may be perceived as an early indication of antibody formation and serve as a surrogate for later changes in efficacy and safety in individual subjects. Given the substantial increase in number of biological products, including biosimilars, there is an urgent need to quantitatively predict and quantify the immune response and any consequential changes in TP pharmacokinetics. The purpose of this communication is to review the utility of population-based modeling and simulation approaches developed to date for investigating the development of an immune response and assessing its impact on TP pharmacokinetics. Two examples of empirical modeling approaches for pharmacokinetic assessment are presented. The first example presents methods to analyze pharmacokinetic data in the presence of anti-drug antibody (ADA) and confirm the effect of immunogenicity on TP pharmacokinetics in early phases of drug development. The second example provides a framework to analyze pharmacokinetic data in the absence or with very low incidence of ADA and confirm with enough power the lack of an immunogenicity effect on TP pharmacokinetics in late phases of drug development. Finally, a theoretical mechanism-based modeling framework is presented to mathematically relate the complex interaction among TP, their targets, and ADA.
*23139019* 23139019 Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials. AAPS J 2013; 15 (1): 195-218
Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn?s disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, ?-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months. Curcumin?s pleiotropic activities emanate from its ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF??B, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-?, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.
*23143785* 23143785 Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics. AAPS J 2013; 15 (1): 30-40
The availability of highly sensitive immunoassays enables the detection of antidrug antibody (ADA) responses of various concentrations and affinities. The analysis of the impact of antibody status on drug pharmacokinetics (PK) is confounded by the presence of low-affinity or low-concentration antibody responses within the dataset. In a phase 2 clinical trial, a large proportion of subjects (45%) developed ADA following weekly dosing with AMG 317, a fully human monoclonal antibody therapeutic. The antibody responses displayed a wide range of relative concentrations (30 ng/mL to >13 ?g/mL) and peaked at various times during the study. To evaluate the impact of immunogenicity on PK, AMG 317 concentration data were analyzed following stratification by dose group, time point, antibody status (positive or negative), and antibody level (relative concentration). With dose group as a stratifying variable, a moderate reduction in AMG 317 levels (<50%) was observed in antibody-positive subjects when compared to antibody-negative subjects, but the difference was not statistically significant in all dose groups. The most significant reduction in AMG 317 levels was revealed when antibody data was stratified by both time point and antibody level. In general, high ADA concentrations (>500 ng/mL) and later time points (week 12) were associated with significantly (up to 97%) lower trough AMG 317 concentrations. The use of quasi-quantitative antibody data and appropriate statistical methods was critical for the most comprehensive evaluation of the impact of immunogenicity on PK.
*23054969* 23054969 Semi-mechanistic Modeling of the Interaction Between the Central and Peripheral Effects in the Antinociceptive Response to Lumiracoxib in Rats. AAPS J 2012; 14 (4): 904-14
The model-based approach was undertaken to characterize the interaction between the peripheral and central antinociceptive effects exerted by lumiracoxib. The effects of intraplantar and intrathecal administrations and of fixed ratio combinations of lumiracoxib simultaneously administered by these two routes were evaluated using the formalin test in rats. Pain-related behavior data, quantified as the number of flinches of the injected paw, were analyzed using a population approach with NONMEM 7. The pain response during the first phase of the formalin test, which was insensitive to lumiracoxib, was modeled using a monoexponential decay. The second phase, which was sensitive to lumiracoxib, was described incorporating synthesis and degradation processes of pain mediators that were recruited locally after tissue injury. Upregulation at the local level and in the central nervous system (CNS) was set to be proportional to the predicted levels of pain mediators in the local (injured) compartment. Results suggest a greater role of upregulated COX-2Local in generating the pain response compared to COX-2CNS. Drug effects were described as inhibition of upregulated COX-2. The model adequately described the time course of nociception after formalin injection in the absence or presence of lumiracoxib administered locally and/or spinally. Data suggest that the overall response is the additive outcome of drug effects at the peripheral and central compartments, with predominance of peripheral mechanisms. Application of modeling opens new perspectives for understanding the overall mechanism of action of analgesic drugs.
*22968496* 22968496 Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics. AAPS J 2012; 14 (4): 781-91
With the advancement of biotechnology in the last two decades, optimized and novel modalities and platforms of biologic moieties have emerged rapidly in drug discovery pipelines. In addition, new technologies for delivering therapeutic biologics (e.g., needle-free devices, nanoparticle complexes), as well as novel approaches for disease treatments (e.g., stem cell therapy, individualized medicine), continue to be developed. While pharmacokinetic studies are routinely carried out for therapeutic biologics, experiments that elucidate underlying mechanisms for clearance and biodistribution or identify key factors that govern absorption, distribution, metabolism, and excretion (ADME) of biologics often are not thoroughly conducted. Realizing the importance of biologics as therapeutic agents, pharmaceutical industry has recently begun to move the research focus from small molecules only to a blended portfolio consisting of both small molecules and biologics. This trend brings many opportunities for scientists working in the drug disposition research field. In anticipation of these opportunities and associated challenges, this review highlights impact of ADME studies on clinical and commercial success of biologics, with a particular focus on emerging applications and technologies and linkage with mechanistic pharmacokinetic/pharmacodynamic modeling and biomarker research.
*22864668* 22864668 Drug Repurposing: Far Beyond New Targets for Old Drugs. AAPS J 2012; 14 (4): 759-63
Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach is of interest primarily because we continue to face significant gaps in the drug?target interactions matrix and to accumulate safety and efficacy data during clinical studies. Collecting and making publicly available as much data as possible on the target profile of drugs offer opportunities for drug repurposing, but may limit the commercial applications by patent applications. Certain clinical applications may be more feasible for repurposing than others because of marked differences in side effect tolerance. Other factors that ought to be considered when assessing drug repurposing opportunities include relevance to the disease in question and the intellectual property landscape. These activities go far beyond the identification of new targets for old drugs.
*22826034* 22826034 Absorption, Distribution, Metabolism, and Excretion (ADME) Studies of Biotherapeutics for Autoimmune and Inflammatory Conditions. AAPS J 2012; 14 (4): 714-27
Biotherapeutics are becoming an increasingly common drug class used to treat autoimmune and other inflammatory conditions. Optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of biotherapeutics is crucial for clinical, as well as commercial, success of these drugs. This review focuses on the common questions and challenges in ADME optimization of biotherapeutics for inflammatory conditions. For these immunomodulatory and/or immunosuppressive biotherapeutics, special consideration should be given to the assessment of the interdependency of ADME profiles, pharmacokinetic/pharmacodynamic (PK/PD) relationships, and immunogenicity profiles across various preclinical species and humans, including the interdependencies both in biology and in assay readouts. The context of usage, such as dosing regimens, extent of disease, concomitant medications, and drug product characteristics may have a direct or indirect (via modulation of immunogenicity) impact on ADME profiles of biotherapeutics. Along these lines, emerging topics include assessments of preexisting reactivity to a biotherapeutic agent, impact of immunogenicity on tissue exposure, and analysis of penetration to normal versus inflamed tissues. Because of the above complexities and interdependences, it is essential to interpret PK, PD, and anti-drug antibody results in an integrated manner. In addition, because of the competitive landscape in autoimmune and inflammatory markets, many pioneering ADME-centric protein engineering and subsequent in vivo testing (such as optimization of novel modalities to extend serum and tissue exposures and to improve bioavailability) are being conducted with biotherapeutics in this therapeutic area. However, the ultimate challenge is demonstration of the clinical relevance (or lack thereof) of modified ADME and immunogenicity profiles.
*22798020* 22798020 What about Pain in Disorders of Consciousness? AAPS J 2012; 14 (3): 437-44
The management and treatment of acute pain is very difficult in non-communicative patients with disorders of consciousness (i.e., vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state), creating an ethical dilemma for caregivers and an emotional burden among both relatives and caregivers. In this review, we summarize recent findings about the neural substrates of nociception and pain in VS/UWS patients as well as recent behavioral assessment methods of nociception specifically designed for patients in altered states of consciousness. We will finally discuss implications for pain treatment in these patients.
*22528502* 22528502 Rapid Sample Size Calculations for a Defined Likelihood Ratio Test-Based Power in Mixed-Effects Models. AAPS J 2012; 14 (2): 176-86
Efficient power calculation methods have previously been suggested for Wald test-based inference in mixed-effects models but the only available alternative for Likelihood ratio test-based hypothesis testing has been to perform computer-intensive multiple simulations and re-estimations. The proposed Monte Carlo Mapped Power (MCMP) method is based on the use of the difference in individual objective function values (?iOFV) derived from a large dataset simulated from a full model and subsequently re-estimated with the full and reduced models. The ?iOFV is sampled and summed (??iOFVs) for each study at each sample size of interest to study, and the percentage of ??iOFVs greater than the significance criterion is taken as the power. The power versus sample size relationship established via the MCMP method was compared to traditional assessment of model-based power for six different pharmacokinetic and pharmacodynamic models and designs. In each case, 1,000 simulated datasets were analysed with the full and reduced models. There was concordance in power between the traditional and MCMP methods such that for 90% power, the difference in required sample size was in most investigated cases less than 10%. The MCMP method was able to provide relevant power information for a representative pharmacometric model at less than 1% of the run-time of an SSE. The suggested MCMP method provides a fast and accurate prediction of the power and sample size relationship.
*22350626* 22350626 AAPS Workshop Report: Strategies to Address Therapeutic Protein?Drug Interactions during Clinical Development. AAPS J 2011; 13 (3): 405-16
Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction. Clinical drug interaction studies are not routinely conducted for TPs because of the logistical constraints in study design to address pharmacokinetic (PK)- and pharmacodynamic (PD)-based interactions. Different pharmaceutical companies have developed their respective question- and/or risk-based approaches for TP-DI based on the TP mechanism of action as well as patient population. During the workshop both company strategies and regulatory perspectives were discussed in depth using case studies; knowledge gaps and best practices were subsequently identified and discussed. Understanding the functional role of target, target expression and their downstream consequences were identified as important for assessing the potential for a TP-DI. Therefore, a question-and/or risk-based approach based upon the mechanism of action and patient population was proposed as a reasonable TP-DI strategy. This field continues to evolve as companies generate additional preclinical and clinical data to improve their understanding of possible mechanisms for drug interactions. Regulatory agencies are in the process of updating their recommendations to sponsors regarding the conduct of in vitro and in vivo interaction studies for new drug applications (NDAs) and biologics license applications (BLAs).
*21630127* 21630127 Translational Biomarkers: from Preclinical to Clinical a Report of 2009 AAPS/ACCP Biomarker Workshop. AAPS J 2011; 13 (2): 274-83
There have been some successes in qualifying biomarkers and applying them to drug development and clinical treatment of various diseases. A recent success is illustrated by a collaborative effort among the US Food and Drug Administration, the European Medicines Agency, and the pharmaceutical industry to provide a set of seven preclinical kidney toxicity biomarkers for drug development. Other successes include, but are not limited to, clinical biomarkers for cancer treatment and clinical management of heart transplant patients. The value of fully qualified surrogate endpoints in facilitating successful drug development is undisputed, especially for diseases in which the traditional clinical outcome can only be assessed in large, multi-year trials. Emerging biomarkers, including chemical genomic or imaging biomarkers, and measurement of circulating tumor cells hold great promise for early diagnosis of disease and as prognostic tests for managing treatment of chronic diseases such as osteoarthritis, Alzheimer disease, cardiovascular disease, and cancer. To advance the success of treating and managing these diseases, efforts are needed to establish the temporal relationship between changes in inflammatory or imaging biomarkers with the progression of the chronic disease, and in the case of cancer, between the extent of circulating cancer cells and tumor progression or remission.
*21448748* 21448748 Performance and Robustness of the Monte Carlo Importance Sampling Algorithm Using Parallelized S-ADAPT for Basic and Complex Mechanistic Models. AAPS J 2011; 13 (2): 212-26
The Monte Carlo Parametric Expectation Maximization (MC-PEM) algorithm can approximate the true log-likelihood as precisely as needed and is efficiently parallelizable. Our objectives were to evaluate an importance sampling version of the MC-PEM algorithm for mechanistic models and to qualify the default estimation settings in SADAPT-TRAN. We assessed bias, imprecision and robustness of this algorithm in S-ADAPT for mechanistic models with up to 45 simultaneously estimated structural parameters, 14 differential equations, and 10 dependent variables (one drug concentration and nine pharmacodynamic effects). Simpler models comprising 15 parameters were estimated using three of the ten dependent variables. We set initial estimates to 0.1 or 10 times the true value and evaluated 30 bootstrap replicates with frequent or sparse sampling. Datasets comprised three dose levels with 16 subjects each. For simultaneous estimation of the full model, the ratio of estimated to true values for structural model parameters (median [5?95% percentile] over 45 parameters) was 1.01 [0.94?1.13] for means and 0.99 [0.68?1.39] for between-subject variances for frequent sampling and 1.02 [0.81?1.47] for means and 1.02 [0.47?2.56] for variances for sparse sampling. Imprecision was ?25% for 43 of 45 means for frequent sampling. Bias and imprecision was well comparable for the full and simpler models. Parallelized estimation was 23-fold (6.9-fold) faster using 48 threads (eight threads) relative to one thread. The MC-PEM algorithm was robust and provided unbiased and adequately precise means and variances during simultaneous estimation of complex, mechanistic models in a 45 dimensional parameter space with rich or sparse data using poor initial estimates.
*21374103* 21374103 Development of a New Pre- and Post-Processing Tool (SADAPT-TRAN) for Nonlinear Mixed-Effects Modeling in S-ADAPT. AAPS J 2011; 13 (2): 201-11
Mechanistic modeling greatly benefits from automated pre- and post-processing of model code and modeling results. While S-ADAPT provides many state-of-the-art parametric population estimation methods, its pre- and post-processing capabilities are limited. Our objective was to develop a fully automated, open-source pre- and post-processor for nonlinear mixed-effects modeling in S-ADAPT. We developed a new translator tool (SADAPT-TRAN) based on Perl scripts. These scripts (a) automatically translate the core model components into robust Fortran code, (b) perform extensive mutual error checks across all input files and the raw dataset, (c) extend the options of the Monte Carlo Parametric Expectation Maximization (MC-PEM) algorithm, and (d) improve the numerical robustness of the model code. The post-processing scripts automatically summarize the results of one or multiple models as tables and, by generating problem specific R scripts, provide an extended series of standard and covariate-stratified diagnostic plots. The SADAPT-TRAN package substantially improved the efficiency to specify, debug, and evaluate models and enhanced the flexibility of using the MC-PEM algorithm for parallelized estimation in S-ADAPT. The parameter variability model can take any combination of normally, log-normally, or logistically distributed parameters and the SADAPT-TRAN package can automatically generate the Fortran code required to specify between occasion variability. Extended estimation features are available to avoid local minima, estimate means with negligible variances, and estimate variances for fixed means. The SADAPT-TRAN package significantly facilitated model development in S-ADAPT, reduced model specification errors, and provided useful error messages for beginner and advanced users. This benefit was greatest for complex mechanistic models.Electronic supplementary material: The online version of this article (doi:10.1208/s12248-011-9257-x) contains supplementary material, which is available to authorized users.
*21369876* 21369876 Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies. AAPS J 2010; 12 (4): 592-601
The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose? and concentration?response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure?response relationships early on.
*20652780* 20652780 Successes Achieved and Challenges Ahead in Translating Biomarkers into Clinical Applications. AAPS J 2010; 12 (3): 243-53
Biomarkers are important tools for identifying and stratifying diseases, predicting their progression and determining the effectiveness, safety, and doses of therapeutic interventions. This is important for common chronic diseases such as diabetic nephropathy, osteoporosis, and rheumatoid arthritis which affect large numbers of patients worldwide. This article summarizes the current knowledge of established and novel biomarkers for each of these diseases as presented at the 2008 AAPS/ACCP joint symposium ?Success Achieved and Challenges Ahead in Translating Biomarkers into Clinical Applications,? in Atlanta, Georgia. The advantages and disadvantages of various proteomic, metabolomic, genomic, and imaging biomarkers are discussed in relation to disease diagnosis and stratification, prognosis, drug development, and potential clinical applications. The use of biomarkers as a means to determine therapeutic interventions is also considered. In addition, we show that biomarkers may be useful for adapting therapies for individual needs by allowing the selection of patients who are most likely to respond or react adversely to a particular treatment. They may also be used to determine whether the development of a novel therapy is worth pursuing by informing crucial go/no go decisions around safety and efficacy. Indeed, regulatory bodies now suggest that effective integration of biomarkers into clinical drug development programs is likely to promote the development of novel therapeutics and more personalized medicine.
*20232184* 20232184 Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease. AAPS J 2010; 12 (1): 33-43
The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.
Pharmakokinetics *19924542* 19924542 Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? AAPS J 2009; 11 (3): 495-510
Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.
Curcumin *19590964* 19590964 Insights into the Substrate Specificity, Inhibitors, Regulation, and Polymorphisms and the Clinical Impact of Human Cytochrome P450 1A2. AAPS J 2009; 11 (3): 481-94
Human CYP1A2 is one of the major CYPs in human liver and metabolizes a variety of clinically important drugs (e.g., clozapine, tacrine, tizanidine, and theophylline), a number of procarcinogens (e.g. benzo[a]pyrene and aflatoxin B1), and several important endogenous compounds (e.g. steroids and arachidonic acids). Like many of other CYPs, CYP1A2 is subject to induction and inhibition by a number of compounds, which may provide an explanation for some drug interactions observed in clinical practice. A large interindividual variability in the expression and activity of CYP1A2 and elimination of drugs that are mainly metabolized by CYP1A2 has been observed, which is largely caused by genetic (e.g., SNPs) and epigenetic (e.g., DNA methylation) and environmental factors (e.g., smoking and comedication). CYP1A2 is primarily regulated by the aromatic hydrocarbon receptor (AhR) and CYP1A2 is induced through AhR-mediated transactivation following ligand binding and nuclear translocation. To date, more than 15 variant alleles and a series of subvariants of the CYP1A2 gene have been identified and some of they have been associated with altered drug clearance and response to drug therapy. For example, lack of response to clozapine therapy due to low plasma drug levels has been reported in smokers harboring the ?163A/A genotype; there is an association between CYP1A21F (?163C>A) allele and the risk for leflunomide-induced host toxicity. The 1F allele is associated with increased enzyme inducibility whereas 1C causes reduced inducibility. Further studies are warranted to explore the clinical and toxicological significance of altered CYP1A2 expression and activity caused by genetic, epigenetic, and environmental factors.
*19590965* 19590965 Inhibitors of the FcRn:IgG Protein?Protein Interaction. AAPS J 2009; 11 (3): ä
The neonatal Fc receptor, FcRn, is responsible for controlling the half-life of IgG antibodies. As a result, inhibitors of FcRn have been investigated as a possible way to modulate IgG half-lives. Such inhibitors could have possible applications in reducing autoantibody levels in autoimmune disease states. To date, monoclonal antibodies, engineered Fc domains, and short peptides have been reported to inhibit FcRn function and modulate IgG half-lives in vivo.
Receptor (Immunoglobulin like) *19499344* 19499344 ?Fit-for-Purpose? Method Validation and Application of a Biomarker (C-terminal Telopeptides of Type 1 Collagen) in Denosumab Clinical Studies. AAPS J 2009; 11 (2): 385-94
Biomarkers are used to study drug effects, exposure?response relationships, and facilitate early decision making during development. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-?B ligand, profoundly inhibits bone resorption. C-terminal telopeptides of type I collagen (CTx), a bone resorption biomarker, provides early indications of denosumab effectiveness and informs protracted clinical outcomes (e.g., bone mineral density). Because of the dynamic relationship between denosumab and CTx, a precise and robust assay was desired. Thus, we adopted a fit-for-purpose approach to modify and validate a commercial CTx diagnostic kit to meet the intended applications of a quantitative pharmacodynamic biomarker for denosumab development. Seven standards were prepared to replace five calibrators provided in the kit. Three quality controls (QC) and two sample controls were used to characterize and monitor assay performance. Robotic workstations were used for standard and QC preparation and assay execution. Method validation experiments were conducted with rigor and procedures similar to those used for drug bioanalysis. The method demonstrated a linear range of 0.0490?2.34 ng/mL with four-parameter logistic regression. Inter-assay total error of validation samples in serum was ?26.7%. Extensive tests were conducted on selectivity in sera from target populations, specificity, stability, parallelism, and dilutional linearity. Applications to samples from numerous clinical studies confirmed that the CTx method was reliable, robust, and fit for use as an early indicator of denosumab effectiveness. Refinement supported the confidence for use in pharmacokinetic/pharmacodynamic modeling, dose selections, correlation to clinical effects, and formulation bioequivalence work.
*19462251* 19462251 Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation. AAPS J 2009; 11 (1): ä
This review covers reports published in the last 5 years on the anti-inflammatory activities of all classes of cannabinoids, including phytocannabinoids such as tetrahydrocannabinol and cannabidiol, synthetic analogs such as ajulemic acid and nabilone, the endogenous cannabinoids anandamide and related compounds, namely, the elmiric acids, and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation. A possible mechanism for these actions is suggested involving increased production of eicosanoids that promote the resolution of inflammation. This differentiates these cannabinoids from cyclooxygenase-2 inhibitors that suppress the synthesis of eicosanoids that promote the induction of the inflammatory process.
Endocannabinoid *19199042* 19199042 Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation. AAPS J 2009; 11 (1): 39-44
The endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA) produces most of its pharmacological effects by binding and activating CB1 and CB2 cannabinoid receptors within the CNS and periphery. However, the actions of AEA are short lived because of its rapid catabolism by fatty acid amide hydrolase (FAAH). Indeed, FAAH knockout mice as well as animals treated with FAAH inhibitors are severely impaired in their ability to hydrolyze AEA as well as a variety of noncannabinoid lipid signaling molecules and consequently possess greatly elevated levels of these endogenous ligands. In this mini review, we describe recent research that has investigated the functional consequences of inhibiting this enzyme in a wide range of animal models of inflammatory and neuropathic pain states. FAAH-compromised animals reliably display antinociceptive and anti-inflammatory phenotypes with a similar efficacy as direct-acting cannabinoid receptor agonists, such as ?9-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa. Importantly, FAAH blockade does not elicit any apparent psychomimetic effects associated with THC or produce reinforcing effects that are predictive of human drug abuse. The beneficial effects caused by FAAH blockade in these models are predominantly mediated through the activation of CB1 and/or CB2 receptors, though noncannabinoid mechanisms of actions can also play contributory or even primary roles. Collectively, the current body of scientific literature suggests that activating the endogenous cannabinoid system by targeting FAAH is a promising strategy to treat pain and inflammation but lacks untoward side effects typically associated with Cannabis sativa.
*19184452* 19184452 Assessment of the Impact of Dosing Time on the Pharmacokinetics/Pharmacodynamics of Prednisolone. AAPS J 2008; 10 (2): ä
Prednisolone is widely used for the treatment of inflammation and auto-immune diseases. It exhibits nonlinear pharmacokinetics (PK); and its induced systemic effects (pharmacodynamics (PD)) are commonly evaluated with two biomarkers, cortisol and blood lymphocytes in plasma. Circadian patterns are observed in both biomarkers. Furthermore, the disease itself may show a circadian pattern. For example, in rheumatoid arthritis patients, better therapeutic outcomes have been reported when prednisolone was administered in the very early morning. The aim of this study is to evaluate the impact of dosing time on the PK/PD of prednisolone with a simulation approach using an interactive algorithm. A series of simulations were performed with either intravenous or oral administration of prednisolone or prednisone. The results showed that the initial or maximum concentration and trough concentration of total prednisolone were lower when the drug was administered in the early morning around 6 am. Oscillation patterns were observed in cumulative cortisol suppression (CCS) and alteration of total lymphocyte trafficking in blood. When the drug was given in the morning within the therapeutic dose range, or around 6 pm for a small dose amount (<1 mg), the minimum CCS and maximum effect on lymphocytes were observed. These results indicated that the PK/PD of prednisolone are time- and dose-dependent, and suggested that it is necessary to consider the application of chronotherapy to achieve better clinical outcomes with fewer side effects of prednisolone, and a PK/PD simulation approach could provide a valuable tool to evaluate and predict time-dependency in the system.
*18581240* 18581240 Nanosystems for simultaneous imaging and drug delivery to T cells. AAPS J 2007; 9 (2): E171-80
The T-cell response defines the pathogenesis of many common chronic disease states, including diabetes, rheumatoid arthritis, and transplant rejection. Therefore, a diagnostic strategy that visualizes this response can potentially lead to early therapeutic intervention, avoiding catastrophic organ failure or prolonged sickness. In addition, the means to deliver a drug dose to those cells in situ with the same specificity used to image those cells would provide for a powerful therapeutic alternative for many disease states involving T cells. In this report, we review emerging nanosystems that can be used for simultaneous tracking and drug delivery to those cells. Because of their versatility, these systems?which combine specific receptor targeting with an imaging agent and drug delivery?are suited to both basic science and applications, from developing therapeutic strategies for autoimmune and alloimmune diseases, to noninvasive tracking of pathogenic T-cell migration.
Nanomedicine *17614359* 17614359 Specificity and selectivity evaluations of ligand binding assay of protein therapeutics against concomitant drugs and related endogenous proteins. AAPS J 2007; 9 (2): E164-70
Macromolecule drugs designed against specific target proteins/receptors have been applied in combination therapies, especially for complex and related diseases such as cancer for synergistic efficacy and alleviation of side effects. Protein therapeutics are typically measured using ligand binding assays (LBA). Evaluating the specificity and selectivity of LBA against their target proteins or in instances where concomitantly administered drugs are given was brought up during a conversation at the 3rd American Association of Pharmaceutical Scienctists/US Food and Drug Administration Bioanalytical Workshop but was not discussed at the meeting sessions. The purpose of this article is to discuss the challenges related to this issue and present a few approaches and experiences to elicit further discussions.Specificity and selectivity tests should be based on the anticipated levels of the individual therapeutics with reference to the dosing regimens defined in the clinical study protocol. When the concomitantly administered compound is available as a pure or well-defined material, various concentrations from zero to above the expected high levels are added to validation samples of the protein therapeutics to assess specificity. Recovery results from spiked samples of target patient populations on concomitant medications can also be compared with those from normal individuals for selectivity. If the drug has an endogenous counterpart, the baseline concentrations of each lot should be subtracted from the test samples in the selectivity assessment. This article illustrates a flexible approach to evaluating specificity and selectivity on samples from target patient populations receiving multiple medications.
*17614358* 17614358 2005 AAPS Biotechnology Conference Open Forum on Aggregation of Protein Therapeutics ? Panel Discussion June 5?8, 2005 San Francisco, CA. AAPS J 2006; 8 (4): E644-54 *18473179* 18473179 Drug discovery from natural sources. AAPS J 2006; 8 (2): E239-53
Organic compounds from terrestrial and marine organisms have extensive past and present use in the treatment of many diseases and serve as compounds of interest both in their natural form and as templates for synthetic modification. Over 20 new drugs launched on the market between 2000 and 2005, originating from terrestrial plants, terrestrial microorganisms, marine organisms, and terrestrial vertebrates and invertebrates, are described. These approved substances, representative of very wide chemical diversity, together with several other natural products or their analogs undergoing clinical trials, continue to demonstrate the importance of compounds from natural sources in modern drug discovery efforts.
*16796374* 16796374 Role of animal models in the study of drug-induced hypersensitivity reactions. AAPS J 2005; 7 (4): E914-21
Drug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very difficult, especially prospective clinical studies. Animal models are vital to most biomedical research, and they are almost the only way to test basis hypotheses of DHRs, such as the involvement of reactive metabolites. However, useful animal models of DHRs are rare because DHRs are also unpredictable in animals. For example, sulfonamide-induced DHRs in large-breed dogs appear to be valid because they are very similar to the DHRs that occur in humans; however, the incidence is only ?0.25%, and large-breed dogs are difficult to use as an animal model. Two more practical models are penicillamine-induced auto-immunity in the Brown Norway rat and nevirapine-induced skin rash in rats. The toxicity in these models is clearly immune mediated. In other models, such as amodiaquine-induced agranulocytosis/hepatotoxicity and halothane-induced hepatotoxicity, the drug induces an immune response but there is no clinical toxicity. This finding suggests that regulatory mechanisms usually limit toxicity. Many of the basic characteristics of the penicillamine and nevirapine models, such as memory and tolerance, are quite different suggesting that the mechanisms are also significantly different. More animal models are needed to study the range of mechanisms involved in DHRs; without them, progress in understanding such reactions is likely to be slow.
*16594644* 16594644 Population pharmacokinetic studies in pediatrics: Issues in design and analysis. AAPS J 2005; 7 (2): E475-87
The current review addresses the following 3 frequently encountered challenges in the design and analysis of population pharmacokinetic studies in pediatrics: (1) body size adjustments during the development of pharmacostatistical models, (2) design and validation of limited sampling strategies, and (3) the integration of historical priors in data analysis and trial simulation. Size adjustments with empiric approaches based on body weight or body surface area have frequently proven as a pragmatic tool to overcome large size differences in a pediatric study population. Allometric size adjustments, however, provide a more mechanistic, physiologically based approach that, if used a priori, allows delineation of the effect of size from that of other covariates that show a high degree of collinearity. The frequent lack of dense data sets in pediatric clinical pharmacology because of ethical and logistic constraints in study design can be overcome with the application of D-optimality-based limited sampling schemes in combination with Bayesian and nonlinear mixed-effects modeling approaches. Empirically based dose selection and clinical trial designs for pediatric clinical pharmacology studies can be improved by applying clinical trial simulation techniques, especially if they integrate adult and pediatric in vitro and/or in vivo data as historic priors. Although integration of these concepts and techniques in population pharmacokinetic analyses is not only limited to pediatric research, their application allows researchers to overcome some major hurdles frequently encountered in pharmacokinetic studies in pediatrics and, thus, provides the basis for additional clinical pharmacology research in this previously insufficiently studied fraction of the general population.
*16353925* 16353925 Evidence of effectiveness: How much can we extrapolate from existing studies? AAPS J 2005; 7 (2): E467-74
Drug development can be a science of extrapolation if the use of a drug exposure-response relationship is embraced and implemented through mechanistically oriented pharmacokinetic (PK)-pharmacodynamic (PD) modeling analysis and clinical trial simulation. The traditional requirement of at least 2 adequate and well-controlled phase III studies by the US Food and Drug Administration for drug approval can be waived in certain situations, substantially reducing the resources and time. In this article, the authors introduce a real drug development case where the chance for this exemption was maximized by actively using PK-PD modeling followed by clinical trial simulation, resulting in faster and more economical introduction of a new dosage regimen to patients.
*16353924* 16353924 Ajulemic acid (IP-751): Synthesis, proof of principle, toxicity studies, and clinical trials. AAPS J 2005; 7 (1): E143-8
Ajulemic acid (CT-3, IP-751,1?,1?-dimethylheptyl-?8 acid) (AJA) has a cannabinoid-derived structure; however, there is no evidence that it produces psychotropic actions when given at therapeutic doses. In a variety of animal assays, AJA shows efficacy in models for pain and inflammation. Furthermore, in the rat adjuvant arthritis model, it displayed a remarkable action in preventing the destruction of inflamed joints. A phase-2 human trial with chronic, neuropathic pain patients suggested that AJA could become a useful drug for treating this condition. Its low toxicity, particularly its lack of ulcerogenicity, further suggests that it will have a highly favorable therapeutic index and may replace some of the current anti-inflammatory/analgesic medications. Studies to date indicate a unique mechanism of action for AJA that may explain its lack of adverse side effects.
*16146336* 16146336 Properties of thalidomide and its analogues: Implications for anticancer therapy. AAPS J 2005; 7 (1): E14-9
Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body s immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal, reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-? (TNF-?), interleukins (IL) 1?, 6, 12, and granulocyte macrophagecolony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-? production and decrease the density of TNF-?-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing, IFN-? levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numer-ous phase II trials in other hematologic and solid tumors.
Thalidomide *16146335* 16146335 Preparation and characterization of gelatin surface modified PLGA microspheres. AAPS PharmSci 2001; 3 (2): 14-24
This study optimized conditions for preparing and characterizing gelatin surface modified poly (lactic-co-glycolic acid) (PLGA) copolymer microspheres and determined this systems interaction with fibronectin. Some gelatin microspheres have an affinity for fibronectin-bearing surfaces; these miscrospheres exploit the interaction between gelatin and fibronectin. PLGA copolymer microspheres were selected because they have reproducible and slowrelease characteristics in vivo. The PLGA microspheres were surface modified with gelatin to impart fibronectin recognition. Dexamethasone was incorporated into these microspheres because dexamethasone is beneficial in chronic human diseases associated with extra fibronectin expression (eg, cardiovascular disease, inflammatory disorders, rheumatoid arthritis). The gelatin surface modified PLGA microspheres (prepared by adsorption, conjugation, and spray coating) were investigated and characterized by encapsulation efficiency, particle size, in vitro release, and affinity for fibronectin. The gelatincoated PLGA microspheres had higher interaction with fibronectin compared with the other gelatin surface modified PLGA microspheres (adsorption and conjugation). Dexamethasone was released slowly (over 21 days) from gelatin surface modified PLGA microspheres.
*11741261* 11741261 Chronotherapeutic Drug Delivery of Ketoprofen and Ibuprofen for Improved Treatment of Early Morning Stiffness in Arthritis Using Hot-Melt Extrusion Technology. AAPS PharmSciTech 2018; 19 (6): 2700-9
This work developed a chronotherapeutic drug delivery system (CTDDS) utilizing a potential continuous hot-melt extrusion (HME) technique. Ketoprofen (KTP) and ibuprofen (IBU) were used as two separate model drugs. Eudragit S100 (ES100) was the matrix-forming agent, and ethyl cellulose (EC) (2.5 and 5%) was the release-retarding agent. A 16-mm extruder was used to develop the CTDDS to pilot scale. The obtained extrudate strands were transparent, indicating that the drugs were homogeneously dispersed in the matrix in an amorphous form, confirmed by both differential scanning calorimetry and powder X-ray diffraction. The strands were pelletized into 1, 2, and 3 mm size pellets. A 100% drug release from 1, 2, and 3 mm pellets with 2.5% EC was observed at 12, 14, and 16 h, whereas the drug release was sustained for 14, 16, and 22 h from 5% EC pellets, respectively, for KTP. The release characteristics of IBU were similar to those of KTP with modest variations in release at lag time. The in vitro drug release study conducted in three-stage dissolution media showed a desired lag time of 6 h. The percent drug release from 1, 2, and 3 mm pellets with 40% drug load showed < 20% release from all formulations at 6 h. The amount of ethyl cellulose and pellet size significantly affected drug release. Formulations of both KTP and IBU were stable for 4 months at accelerated stability conditions of 40°C/75% RH. In summary, HME is a novel technique for developing CTDDS.
*29968041* 29968041 Design and Evaluation of a Novel Felbinac Transdermal Patch: Combining Ion-Pair and Chemical Enhancer Strategy. AAPS PharmSciTech 2016; 17 (2): 262-71
The aim of this study was to design a novel felbinac (FEL) patch with significantly higher (P?0.05) skin permeation amount than the commercial product SELTOUCH® using ion-pair and chemical enhancer strategy, overcoming the disadvantage of the large application area of SELTOUCH®. Six complexes of FEL with organic amines diethylamine (DEA), triethylamine (TEA), N-(2?-hydroxy-ethanol)-piperdine (HEPP), monoethanolamine (MEtA), diethanolamine (DEtA), and triethanolamine (TEtA) were prepared by ion-pair interaction, and their formation were confirmed by differential scanning calorimetry (DSC), powder X-ray diffraction (pXRD), infared spectroscopy (IR), and proton nuclear magnetic resonance spectroscopy (1H-NMR). Subsequently, the effect of ion-pair complexes and chemical enhancers were investigated through in vitro and in vivo experiments using rabbit abdominal skin. Results showed that FEL-TEA was the most potential candidate both in isopropyl palmitate (IPP) solution and transdermal patches. Combining use of 10% N-dodecylazepan-2-one (Azone), the optimized FEL-TEA patch achieved a flux of 18.29?±?2.59 ?g/cm2/h, which was twice the amount of the product SELTOUCH® (J?=?9.18?±?1.26 ?g/cm2/h). Similarly, the area under the concentration curve from time 0 to time t (AUC0-t) in FEL-TEA patch group (15.94?±?3.58 h.?g/mL) was also twice as that in SELTOUCH® group (7.31?±?1.16 h.?g/mL). Furthermore, the in vitro skin permeation results of FEL-TEA patch was found to have a good correlation with the in vivo absorption results in rabbit. These findings indicated that a combination of ion-pair and chemical enhancer strategy could be useful in developing a novel transdermal patch of FEL.
*26070544* 26070544 In Vivo Evaluation of 5-ASA Colon-Specific Tablets Using Experimental-Induced Colitis Rat Animal Model. AAPS PharmSciTech 2015; 16 (6): 1445-54
Colonic drug delivery is intended not only for local treatment in inflammatory bowel disease (IBD) but also for systemic delivery of therapeutics. Intestinal myeloperoxidase (MPO) determination could be used to estimate the average level of inflammation in colon as well as to determine the efficacy of drugs to be used in the treatment of inflammatory bowel diseases or study the specificity of dosage forms to be used for colonic targeting of anti-inflammatory drugs. Colonic prodrug sulfasalazine (SASP) gets metabolized to give 5-aminosalicylic acid (5-ASA), which is the active portion of SASP. However, when given orally, 5-ASA is absorbed in upper part of gastrointestinal tract (GIT) and not made available in colon. In the present study, colon-targeted delivery of 5-ASA was achieved by formulating tablets with two natural polymers namely guar gum and pectin using compression coating method. Colonic specificity of 5-ASA tablets (prepared using guar gum and pectin as polymers) was evaluated in vitro using simulated fluids mimicking in vivo environment as well as in vivo method using chemically (2,4,6-trinitrobenzenesulfonic acid and acetic acid)-induced colitis rat model. Both colon-specific formulations of 5-ASA (guar gum and pectin) were observed to be more effective in reducing inflammation in chemically induced colitis rat models when compared to colon-specific prodrug sulfasalazine as well as conventional 5-ASA administered orally.
*26017284* 26017284 A Novel Approach to Flurbiprofen Pulsatile Colonic Release: Formulation and Pharmacokinetics of Double-Compression-Coated Mini-Tablets. AAPS PharmSciTech 2015; 16 (6): 1465-73
A significant plan is executed in the present study to study the effect of double-compression coating on flurbiprofen core mini-tablets to achieve the pulsatile colonic delivery to deliver the drug at a specific time as per the patho-physiological need of the disease that results in improved therapeutic efficacy. In this study, pulsatile double-compression-coated tablets were prepared based on time-controlled hydroxypropyl methylcellulose K100M inner compression coat and pH-sensitive Eudragit S100 outer compression coat. Then, the tablets were evaluated for both physical evaluation and drug-release studies, and to prove these results, in vivo pharmacokinetic studies in human volunteers were conducted. From the in vitro drug-release studies, F6 tablets were considered as the best formulation, which retarded the drug release in the stomach and small intestine (3.42?±?0.12% in 5 h) and progressively released to the colon (99.78?±?0.74% in 24 h). The release process followed zero-order release kinetics, and from the stability studies, similarity factor between dissolution data before and after storage was found to be 88.86. From the pharmacokinetic evaluation, core mini-tablets producing peak plasma concentration (Cmax) was 14,677.51?±?12.16 ng/ml at 3 h Tmax and pulsatile colonic tablets showed Cmax?=?12,374.67?±?16.72 ng/ml at 12 h Tmax. The area under the curve for the mini and pulsatile tablets was 41,238.52 and 72,369.24 ng-h/ml, and the mean resident time was 3.43 and 10.61 h, respectively. In conclusion, development of double-compression-coated tablets is a promising way to achieve the pulsatile colonic release of flurbiprofen.
*26017285* 26017285 Radio Frequency-Activated Nanoliposomes for Controlled Combination Drug Delivery. AAPS PharmSciTech 2015; 16 (6): 1335-43
This work was conducted in order to design, characterize, and evaluate stable liposomes containing the hydrophobic drug raloxifene HCl (RAL) and hydrophilic doxycycline HCl (DOX), two potentially synergistic agents for treating osteoporosis and other bone lesions, in conjunction with a radio frequency-induced, hydrophobic magnetic nanoparticle-dependent triggering mechanism for drug release. Both drugs were successfully incorporated into liposomes by lipid film hydration, although combination drug loading compromised liposome stability. Liposome stability was improved by reducing the drug load and by including Pluronics® (PL) in the formulations. DOX did not appear to interact with the phospholipid membranes comprising the liposomes, and its release was maximized in the presence of radio frequency (RF) heating. In contrast, differential scanning calorimetry (DSC) and phosphorus-31 nuclear magnetic resonance (31P-NMR) analysis revealed that RAL developed strong interactions with the phospholipid membranes, most notably with lipid phosphate head groups, resulting in significant changes in membrane thermodynamics. Likewise, RAL release from liposomes was minimal, even in the presence of RF heating. These studies may offer useful insights into the design and optimization of multidrug containing liposomes. The effects of RAL on liposome characteristics and drug release performance underscore the importance of appropriate physical-chemical analysis in order to identify and characterize drug-lipid interactions that may profoundly affect liposome properties and performance early in the formulation development process.
*25899799* 25899799 Design and Evaluation of the Highly Concentrated Human IgG Formulation Using Cyclodextrin Polypseudorotaxane Hydrogels. AAPS PharmSciTech 2015; 16 (6): 1290-8
To achieve the potent therapeutic effects of human immunoglobulin G (IgG), highly concentrated formulations are required. However, the stabilization for highly concentrated human IgG is laborious work. In the present study, to investigate the potentials of polypseudorotaxane (PPRX) hydrogels consisting of polyethylene glycol (PEG) and ?- or ?-cyclodextrin (?- or ?-CyD) as pharmaceutical materials for highly concentrated human IgG, we designed the PPRX hydrogels including human IgG and evaluated their pharmaceutical properties. The ?- and ?-CyDs formed PPRX hydrogels with PEG (M.W. 20,000) even in the presence of highly concentrated human IgG (>100 mg/mL). According to the results of 1H-NMR, powder X-ray diffraction, and Raman microscopy, the formation of human IgG/CyD PPRX hydrogels was based on physical cross-linking arising from their columnar structures. The release profiles of human IgG from the hydrogels were in accordance with the non-Fickian diffusion model. Importantly, the stabilities of human IgG included into the hydrogels against thermal and shaking stresses were markedly improved. These findings suggest that PEG/CyD PPRX hydrogels are useful to prepare the formulation for highly concentrated human IgG.
*25776984* 25776984 Tolerability of High-Volume Subcutaneous Injections of a Viscous Placebo Buffer: A Randomized, Crossover Study in Healthy Subjects. AAPS PharmSciTech 2015; 16 (5): 1101-7
Monoclonal antibody biotherapeutics are often administered by subcutaneous (SC) injection. Due to dose requirements and formulation limitations, SC injections >1 mL are often required. We used a viscous placebo buffer (5 cP), characteristic of a high-concentration antibody formulation, to investigate the effect of dose volume and injection rate on the tolerability of higher-volume SC injections. In this randomized, crossover, single-center study, 48 healthy adults received one 1.2-mL bolus injection over 5 s and three 3.5-mL injections over 1, 4, and 10 min in different abdominal quadrants, with each injection separated by approximately 2 h. The primary objective was to compare pain scores associated with the injections, immediately after administration and 1 h later, using a 100-mm visual analog scale (VAS). Secondary objectives included assessment of adverse events, including injection site reactions and swelling. Mean age was 38.4 (11.6) years and 20 subjects (42%) were female. Lowest mean VAS score was for the 10-min (6.83 mm) and highest for the 1-min injection (19.13 mm). One hour after administration, mean VAS scores were <3.5 mm for all injections. Swelling was similar among the three 3.5-mL injections. After needle removal, leakage occurred following 14 (29%) 1.2-mL injections, eight (17%) 4-min injections, five (10%) 1-min injections, and four (8%) 10-min injections. Fifteen subjects (31%) experienced an adverse event, none of which was serious, fatal, or led to study discontinuation. All injection durations were well tolerated, suggesting a single large-volume SC injection of a biotherapeutic agent could be used instead of multiple injections.
*25693652* 25693652 Phytantriol-Based In Situ Liquid Crystals with Long-Term Release for Intra-articular Administration. AAPS PharmSciTech 2015; 16 (4): 846-54
The purpose of this study was to develop an injectable in situ liquid crystal formulation for intra-articular (IA) administration, and in situ forming a viscous liquid crystalline gel with long-term release of sinomenine hydrochloride (SMH) upon water absorption. The pseudo-ternary phase diagram of phytantriol (PT)-ethanol (ET)-water was constructed, and isotropic solutions were chosen for further optimization. The physicochemical properties of isotropic solutions were evaluated, and the phase structures of liquid crystalline gels formed by isotropic solutions in excess water were confirmed by crossed polarized light microscopy (CPLM) and small-angle X-ray scattering (SAXS). In vitro drug release studies were conducted by using a dialysis membrane diffusion method. The optimal in situ cubic liquid crystal (ISV2) (PT/ET/water, 64:16:20, w/w/w) loaded with 6 mg/g of SMH showed a suitable pH, showed to be injectable, and formed a cubic liquid crystalline gel in situ with minimum water absorption within the shortest time. The optimal ISV2 was able to sustain the drug release for 6 days. An in situ hexagonal liquid crystal (ISH2) system was prepared by addition of 5% vitamin E acetate (VitEA) into PT in the optimal ISV2 system to improve the sustained release of SMH. This ISH2 (PT/VitEA/ET/water, 60.8:3.2:16:20, w/w/w/w) was an injectable isotropic solution with a suitable pH range. The developed ISH2 was found to be able to sustain the drug release for more than 10 days and was suitable for IA injection for the treatment of rheumatoid arthritis (RA).
*25573438* 25573438 Proniosomal Oral Tablets for Controlled Delivery and Enhanced Pharmacokinetic Properties of Acemetacin. AAPS PharmSciTech 2015; 16 (2): 375-83
Free-flowing proniosomal powders of acemetacin (AC) were prepared using the slurry method and maltodextrin as carrier. Positively charged proniosomes composed of 70:20:10 of Span 60/cholesterol (Chol)/stearylamine (SA), respectively, were successively compressed into tablets using direct compression method. The tablets were characterized for weight variability, friability, hardness, drug content uniformity, and dissolution properties. The in vivo evaluation of the prepared proniosomes (powder or tablet forms) after oral administration was investigated by the determination of AC and its active metabolite indomethacin (IND) in the blood of albino rabbits. Results indicated that the increase of Chol from 10% to 20% markedly reduced the efflux of the drug. Further Chol addition from 30% to 50% led to increased AC release rates. The proniosome tablets of AC showed greater hardness and disintegration time and less friability than AC plain tablets. The dissolution of proniosomal tablets indicated a lower drug release percentage compared to powdered proniosomes and AC plain tablets. The mean pharmacokinetic parameters of AC and IND from different formulations indicated increased t1/2 and area under the curve (AUC) of both AC and IND for proniosomal tablets compared with both proniosomal powders and AC plain tablets. This study suggested the formulation of AC proniosomal powder into tablets to control and extend its pharmacologic effects.
*25319057* 25319057 Liquid Crystalline Systems for Transdermal Delivery of Celecoxib: In Vitro Drug Release and Skin Permeation Studies. AAPS PharmSciTech 2014; 15 (6): 1468-75
Liquid crystalline systems of monoolein/water could be a promising approach for the delivery of celecoxib (CXB) to the skin because these systems can sustain drug release, improve drug penetration into the skin layers and minimize side effects. This study evaluated the potential of these systems for the delivery of CXB into the skin based on in vitro drug release and skin permeation studies. The amount of CXB that permeated into and/or was retained in the skin was assayed using an HPLC method. Polarizing light microscopy studies showed that liquid crystalline systems of monoolein/water were formed in the presence of CXB, without any changes in the mesophases. The liquid crystalline systems decreased drug release when compared to control solution. Drug release was independent of the initial water content of the systems and CXB was released from cubic phase systems, irrespective of the initial water content. The systems released the CXB following zero-order release kinetics. In vitro drug permeation studies showed that cubic phase systems allowed drug permeation and retention in the skin layers. Cubic phase systems of monoolein/water may be promising vehicles for the delivery of CXB in/through the skin because it improved CXB skin permeation compared with the control solution.
*24980082* 24980082 Nanoparticle Ligand Presentation for Targeting Solid Tumors. AAPS PharmSciTech 2014; 15 (5): 1345-54
Among the many scientific advances to come from the study of nanoscience, the development of ligand-targeted nanoparticles to eliminate solid tumors is predicted to have a major impact on human health. There are many reports describing novel designs and testing of targeted nanoparticles to treat cancer. While the principles of the technology are well demonstrated in controlled lab experiments, there are still many hurdles to overcome for the science to mature into truly efficacious targeted nanoparticles that join the arsenal of agents currently used to treat cancer in humans. One of these hurdles is overcoming unwanted biodistribution to the liver while maximizing delivery to the tumor. This almost certainly requires advances in both nanoparticle stealth technology and targeting. Currently, it continues to be a challenge to control the loading of ligands onto polyethylene glycol (PEG) to achieve maximal targeting. Nanoparticle cellular uptake and subcellular targeting of genes and siRNA also remain a challenge. This review examines the types of ligands that have been most often used to target nanoparticles to solid tumors. As the science matures over the coming decade, careful control over ligand presentation on nanoparticles of precise size, shape, and charge will likely play a major role in achieving success.
*24927668* 24927668 A New Lipid-Based Nano Formulation of Vinorelbine. AAPS PharmSciTech 2014; 15 (5): 1138-48
Vinorelbine (VLB) is a semi-synthetic Vinca alkaloid which is currently used in treatment of different cancer types mainly advanced breast cancer (ABC) and advanced/metastatic non-small cell lung cancer (NSCLC). However, its marketed formulation has been reported to have serious side effects, such as granulocytopenia, which is the major dose-limiting toxicity. Other unwanted effects include venous discoloration and phlebitis proximal to the site of injection, as well as localized rashes and urticaria, blistering, and skin sloughing. Our long-term aim in synthesizing a novel nanomicellar vinorelbine formulation is to reduce or even eliminate these side effects and increase drug activity by formulating the drug in a lipid-based system as a nanomedicine targeted to the site of action. To this end, the purpose of this study was to prepare, characterize, and determine the in vitro efficacy of vinorelbine-loaded sterically stabilized, biocompatible, and biodegradable phospholipid nanomicelles (SSM; size, ?15 nm). Our results indicated that vinorelbine incorporate at high quantities and within the interface between the core and palisade sections of the micelles. Incorporation ratio of drug within sterically stabilized micelles increased as the total amount of drug in the system increased, and no drug particles were formed at the highest drug concentrations tested. The nanomicellar formulation of vinorelbine was ?6.7-fold more potent than vinorelbine dissolved in DMSO on MCF-7 cell line. Collectively, these data indicate that vinorelbine-loaded SSM can be developed as a new, safe, stable, and effective nanomedicine for the treatment of breast and lung cancers.
*24871553* 24871553 Considerations for a Pediatric Biopharmaceutics Classification System (BCS): Application to Five Drugs. AAPS PharmSciTech 2014; 15 (3): 601-11
It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m2 adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.
*24557773* 24557773 Formulation and Optimization of Nonionic Surfactants Emulsified Nimesulide-Loaded PLGA-Based Nanoparticles by Design of Experiments. AAPS PharmSciTech 2014; 15 (1): 161-76
This investigation aimed to develop nimesulide (NMS)-loaded poly(lactic-co-glycolic acid) (PLGA)-based nanoparticulate formulations as a biodegradable polymeric drug carrier to treat rheumatoid arthritis. Polymeric nanoparticles (NPs) were prepared with two different nonionic surfactants, vitamin E d-?-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and poly(vinyl alcohol) (PVA), using an ultrasonication solvent evaporation technique. Nine batches were formulated for each surfactant using a 32 factorial design for optimal concentration of the emulsifying agents, 0.03?0.09% for vitamin E TPGS and 2?4% for PVA. The surfactant percentage and the drug/polymer ratio (1:10, 1:15, 1:20) of the NMS-loaded NPs were investigated based on four responses: encapsulation efficiency, particle size, the polydispersity index, and the surface charge. The response surface plots and linearity curves indicated a relationship between the experiment?s responses and a set of independent variables. The NPs produced with both surfactants exhibited a negative surface charge, and scanning electron micrographs revealed that all of the NPs were spherical in shape. A narrower size distribution and higher drug loadings were achieved in PVA-emulsified PLGA NPs than in the vitamin E TPGS emulsified. Decreasing amounts of both nonionic surfactants resulted in a reduction in the emulsion?s viscosity, which led to a decrease in the particle size of NPs. According to the ANOVA results obtained in this present research, vitamin E TPGS exhibited the best correlation between the independent variables, namely drug/polymer ratio and the surfactant percentage, and the dependent variables (encapsulation efficiency R2?=?0.9603, particle size R2?=?0.9965, size distribution R2?=?0.9899, and surface charge R2?=?0.8969) compared with PVA.
*24222270* 24222270 Niosomal Gel of Lornoxicam for Topical Delivery: In vitro Assessment and Pharmacodynamic Activity. AAPS PharmSciTech 2013; 14 (3): 1072-82
Lornoxicam is a potent oxicam class of non steroidal anti-inflammatory agent, prescribed for mild to moderate pain and inflammation. Niosomal gel of lornoxicam was developed for topical application. Lornoxicam niosomes (Lor-Nio) were fabricated by thin film hydration technique. Bilayer composition of niosomal vesicles was optimized. Lor-Nio dispersion was characterized by DSC, XRD, and FT-IR. Morphological evaluation was performed by scanning electron microscopy (SEM). Lor-Nio dispersion was incorporated into a gel using 2% w/w Carbopol 980 NF. Rheological and texture properties of Lor-Nio gel formulation showed suitability of the gel for topical application. The developed formulation was evaluated for in vitro skin permeation and skin deposition studies, occlusivity test and skin irritation studies. Pharmacodynamic activity of the Lor-Nio gel was performed by carragenan-induced rat paw model. Optimized Lor-Nio comprised of Span 60 and cholesterol in a molar ratio of 3:1 with 30 ?M dicetyl palmitate as a stabilizer. It had particle size of 1.125?±?0.212 ?m (d90), with entrapment efficiency of 52.38?±?2.1%. DSC, XRD, and IR studies showed inclusion of Lor into niosomal vesicles. SEM studies showed spherical closed vesicular structure with particles in nanometer range. The in vitro skin permeation studies showed significant improvement in skin permeation and skin deposition for Lor-Nio gel (31.41?±?2.24 ?g/cm2, 30.079?±?1.2 ?g/cm2) over plain lornoxicam gel (7.37?±?1.27 ?g/cm2, 6.6?±?2.52 ?g/cm2). The Lor-Nio gel formulation showed enhanced anti-inflammatory activity by exhibiting mean edema inhibition (87.69?±?1.43%) which was significantly more than the plain lornoxicam gel (53.84?±?2.21%).
*23818079* 23818079 Ophthalmic Delivery of Brinzolamide by Liquid Crystalline Nanoparticles: In Vitro and In Vivo Evaluation. AAPS PharmSciTech 2013; 14 (3): 1063-71
Brinzolamide (BLZ) is a drug used to treat glaucoma; however, its use is restricted due to some unwanted adverse events. The goal of this study was to develop BLZ-loaded liquid crystalline nanoparticles (BLZ LCNPs) and to figure out the possibility of LCNPs as a new therapeutic system for glaucoma. BLZ LCNPs were produced by a modified emulsification method and their physicochemical aspects were estimated. In vitro release study revealed BLZ LCNPs displayed to some extent prolonged drug release behavior in contrast to that of BLZ commercial product (Azopt®). The ex vivo apparent permeability coefficient of BLZ LCNP systems demonstrated a 3.47-fold increase compared with that of Azopt®. The pharmacodynamics was checked over by calculating the percentage fall in intraocular pressure and the pharmacodynamic test showed that BLZ LCNPs had better therapeutic potential than Azopt®. Furthermore, the in vivo ophthalmic irritation was evaluated by Draize test. In conclusion, BLZ LCNPs would be a promising delivery system used for the treatment of glaucoma, with advantages such as lower doses but maintaining the effectiveness, better ocular bioavailability, and patient compliance compared with Azopt®.
*23813437* 23813437 Studies on Tolfenamic Acid?Chitosan Intermolecular Interactions: Effect of pH, Polymer Concentration and Molecular Weight. AAPS PharmSciTech 2013; 14 (2): 870-9
Solid-state properties of tolfenamic acid (TA) and its complexes with chitosan (CT) have been studied. Effect of medium pH, molecular weight of polymer and its different concentrations on these TA?CT complexes were studied in detail. Low and medium molecular weight CT have been used in different ratios at pH ranging from 4 to 6 and freeze-drying technique has been employed to modify the appearance of crystalline TA. Physical properties of the formed complexes have been studied by employing X-ray diffraction, differential scanning calorimetry and scanning electron microscopy; chemical structure has been studied using Fourier transform infrared spectroscopy. The results showed that both forms of the polymer exhibited complete conversion in 1:8 ratio at pH 4, 1:4 at pH 5 and 1:1 at pH 6 indicating a marked effect of pH on drug?polymer complexation. The percent crystallinity calculations indicated low molecular weight CT slightly more effective than the other form. No changes in the complexes have been observed during the 12 week storage under controlled conditions. Both forms of CT at different pH values indicated retardation of recrystallization in TA during cooling of the melt from 1:1 ratios exhibiting formation of strong intermolecular hydrogen bonding between the drug and the polymer.
*23620261* 23620261 Inulin-Based Tablet in Capsule Device for Variable Multipulse Delivery of Aceclofenac: Optimization and In Vivo Roentgenography. AAPS PharmSciTech 2013; 14 (2): 736-47
The aim of the study was to develop single-unit tablet in capsule system of aceclofenac for the treatment of late night pain and morning stiffness associated with rheumatoid arthritis. The system was conceptualized as a three-component design (1) a hard gelatin enteric-coated capsule (for carrying two pulses), (2) first-pulse granules (for rapid release in intestine), and (2) second-pulse matrix tablet (for slow release in colon). An appropriate integration of pH-sensitive (Eudragit S100) and bacteria-responsive (inulin) functions, on the basis of 32 factorial design, led to formulation of TICS 1?9 that were screened for in vitro release. TICS 2 with biphasic drug release of 98.64% from first-pulse granules in simulated intestinal fluid (12 h) and 97.82% from second-pulse matrix tablet in simulated colonic fluid (24 h) was the optimized formulation that exhibited Fickian diffusion of drug (n?=?0.363). In vivo fluoroscopy in rats traced the intact tablet to colon in 7.5 h that got eroded at the tenth hour. This demonstrated the colon-specific delivery of the matrix tablet affirming the potential of the system to obviate the need for two-time administration of drug at odd hours. The experimental design was validated by extra design check point, and diffuse reflectance spectroscopy and DSC revealed absence of chemical interaction between the formulation excipients.
*23615771* 23615771 Simultaneous Determination of EDTA, Sorbic Acid, and Diclofenac Sodium in Pharmaceutical Preparations Using High-Performance Liquid Chromatography. AAPS PharmSciTech 2013; 14 (2): 764-9
A simple high-performance liquid chromatographic method for simultaneous determination of ethylenediaminetetraacetic acid (EDTA), sorbic acid, and diclofenac sodium was developed and validated. Separation was achieved on a C18 column (10 cm?×?4.6 mm) using gradient elution. The mobile phase consisted of acetonitrile?ammonium dihydrogen phosphate buffer solution (0.01 M, pH?=?2.5, containing 0.8% tetra-n-butyl ammonium hydroxide). The detector wavelength was set at 254 nm. Under these conditions, separation of three compounds was achieved in less than 10 min. The effect of two metal salts and metal concentration on peak area of EDTA was investigated. The pH effect on retention of EDTA and sorbic acid was studied. The method showed linearity for EDTA, sorbic acid, and diclofenac in the ranges of 2.5?100.0, 5.0?200.0, and 20.0?120.0 ?g/mL, respectively. The within- and between-day relative standard deviations ranged from 0.52 to 1.94%, 0.50 to 1.34%, and 0.78 to 1.67% for EDTA, sorbic acid, and diclofenac, respectively. The recovery of EDTA, sorbic acid, and diclofenac from pharmaceutical preparation ranged from 96.0?102.0%, 99.7?101.5%, to 97.0?102.5%, respectively. To the best of our knowledge, this is the first report about simultaneous determination of EDTA, sorbic acid, and diclofenac.
*23585291* 23585291 Influence of Microcrystal Formulation on In Vivo Absorption of Celecoxib in Rats. AAPS PharmSciTech 2013; 14 (2): 719-26
The objective of this study was to prepare celecoxib microcrystals using different stabilizers in order to evaluate the influence of microcrystal formulation on the in vitro dissolution rate and in vivo absorption after oral administration of celecoxib in rats. Three celecoxib microcrystals (MC1, MC2, and MC3) were prepared using solvent change method. Microcrystals were evaluated for morphology, particle size, crystallinity, solubility, in vitro dissolution, and in vivo absorption in rats. Scanning electron microscopy images showed distinct differences in the morphologies and dimensions of various celecoxib microcrystals. The particle size of all microcrystals was significantly (P?0.05) reduced relative to plain celecoxib. The DSC and XRD results revealed that MC1 retain drug crystallinity relative to control crystals, MC2, and MC3. All microcrystals showed marked increase in the drug dissolution parameters particularly MC1 that exhibited a prompt drug release and significantly (P?0.05) higher values of % dissolution efficiency as compared to control celecoxib and the other microcrystals. The influence of microcrystals on the in vivo absorption of celecoxib was studied in rats in comparison to plain drug. The results of in vivo absorption study in rats indicated that MC1 significantly improved the rate and extent of celecoxib absorption than plain celecoxib. The mean relative bioavailability of MC1 formulation to plain celecoxib was 157.55?±?20.18%. In conclusion, microcrystal formulation of celecoxib results not only in an enhancement of dissolution parameters but also improves the bioavailability of celecoxib in rats.
*23543607* 23543607 Development and Validation of a Discriminative Dissolution Test for Betamethasone Sodium Phosphate and Betamethasone Dipropionate Intramuscular Injectable Suspension. AAPS PharmSciTech 2013; 14 (1): 425-34
The intramuscular administration of the injectable suspension betamethasone sodium phosphate (BSP) and betamethasone dipropionate (BD) has immediate therapeutic activity due to solubilized BSP and prolonged activity resulting from the slow release of BD micro-crystals. The purpose of this study was to develop and validate a dissolution method for BD in intramuscular injectable suspensions with detection by high-performance liquid chromatography (HPLC) method. Five commercial products presented a distribution of particle sizes, ranging between 7.43 and 40.25 ?m as measured by laser diffraction. It was also found that particle sizes differed between batches of the same product. The different products were tested using the paddle apparatus, with stirring speeds of 25 and 50 rpm in 300 mL of phosphate buffer; simulated body fluid, muscle fluid, and synovial fluid were used as biorelevant dissolution media at 37?±?0.5°C. It was verified that not only does average particle size affect the dissolution rate, but also the mode and the polydispersity index of the particles. Discriminatory power was obtained using the in vitro dissolution method with 0.1 M sodium phosphate buffer pH 7.4 containing 0.1% sodium lauryl sulfate and a stirring speed of 50 rpm. The HPLC-method is linear, precise, selective, and accurate for the quantification of BSP and BD in dissolution profile testing. This dissolution method can be utilized as a method to control the quality of these injectable suspensions.
*23371786* 23371786 Anti-inflammatory Effect of Seeds and Callus of Nigella sativa L. Extracts on Mix Glial Cells with Regard to Their Thymoquinone Content. AAPS PharmSciTech 2013; 14 (1): 160-7
Anti-inflammatory effect of the alcoholic extracts of N. sativa seeds and its callus on mix glial cells of rat with regard to their thymoquinone (TQ) content was investigated. Callus induction was achieved for explants of young leaf, stem, petiole, and root of N. sativa on solid Murashige and Skoog (MS) medium containing 2,4-D (1 mg/l) and kinetin (2.15 mg/l). TQ content of the alcoholic extracts was measured by HPLC. Total phenols were determined using Folin?Ciocalteu method and antioxidant power was estimated using FRAP tests. The mix glial cells, inflamed by lipopolysaccharide, were subjected to anti-inflammatory studies in the presence of various amounts of TQ and the alcoholic extracts. Viability of the cells and nitric oxide production were measured by MTT and Griess reagent, respectively. The leaf callus obtained the highest growth rate (115.4 mg/day) on MS medium containing 2,4-D (0.22 mg/l) and kinetin (2.15 mg/l). Analyses confirmed that TQ content of the callus of leaf was 12 times higher than that measured in the seeds extract. However, it decreased as the calli aged. Decrease in the TQ content of the callus was accompanied with an increase in its phenolic content and antioxidant ability. Studies on the inflamed rat mix glial cells revealed significant reduction in the nitric oxide production in the presence of 0.2 to 1.6 mg/ml of callus extract and 1.25 to 20 ?l/ml of the seed extracts. However, the extent of the effects is modified assumingly due to the presence of the other existing substances in the extracts.
*23255199* 23255199 Evaluation of Meloxicam-Loaded Cationic Transfersomes as Transdermal Drug Delivery Carriers. AAPS PharmSciTech 2013; 14 (1): 133-40
The aim of this study is to develop meloxicam (MX)-loaded cationic transfersomes as skin delivery carriers and to investigate the influence of formulation factors such as cholesterol and cationic surfactants on the physicochemical properties of transfersomes (i.e., particle size, size distribution, droplet surface charge and morphology), entrapment efficiency, stability of formulations and in vitro skin permeation of MX. The transfersomes displayed a spherical structure. Their size, charge, and entrapment efficiency depended on the composition of cholesterol and cationic surfactants in the formulation. Transfersomes provided greater MX skin permeation than conventional liposomes and MX suspensions. The penetration-enhancing mechanism of skin permeation by the vesicles prepared in this study may be due to the vesicle adsorption to and/or fusion with the stratum corneum. Our results suggest that cationic transfersomes may be promising dermal delivery carriers of MX.
*23242556* 23242556 Reduced Ulcerogenic Potential and Antiarthritic Effect of Chitosan?Naproxen Sodium Complexes. AAPS PharmSciTech 2012; 13 (3): 896-902
The purpose of this research was to address the utility of naproxen sodium?chitosan spray-dried complexes for antiulcer and antiarthritic activities. The cold stress technique was used to examine the ulcerogenic potential of naproxen sodium (NPX) and spray-dried formulations in the different doses. The ulcerations reduced with the dose of spray-dried complexes of naproxen sodium and chitosan. The conspicuous hemorrhagic lesions were visible in the morphological features of the animal treated with naproxen 50 mg/kg (p.o.). Thus, the results suggest that the spray-dried naproxen sodium?chitosan complex (NPXF) was not corrosive to the gastric mucosa at high doses of 50, 100, and 200 mg/kg (p.o.) under stressful conditions. It is evident from the present investigation that NPXF does not possess any ulcerogenic potential in comparison to naproxen which, under stressful conditions, led to the hypersecretion of HCl, culminating to petichial hemorrhages in the gastric mucosa of the animals. The biphasic pattern was observed in the various arthritic parameters. The rise in paw volume, joint diameter, WBC count, arthritis score, and fall in body weight was significantly ameliorated in the animals treated with NPXF (5, 10, and 20 mg/kg, p.o). At the end of the study, slight erythema was visible in the naproxen-treated animals. However, no erythema, redness, or ulcers were visible in the animals treated with NPXF. Thus, the direct compression properties and reduced ulcerogenic activity, combined with the demonstrated solubilizing power and analgesic effect enhancer ability toward the drug, make naproxen sodium?chitosan spray-dried complexes particularly suitable for developing a reduced-dose, fast-release, solid oral dosage form of naproxen.
*22711255* 22711255 Single-Injection HPLC Method for Rapid Analysis of a Combination Drug Delivery System. AAPS PharmSciTech 2012; 13 (2): 605-10
Developing combination drug delivery systems (CDDS) is a challenging but necessary task to meet the needs of complex therapy regimes for patients. As the number of multi-drug regimens being administered increases, so does the difficulty of characterizing the CDDS as a whole. We present a single-step method for quantifying three model therapeutics released from a model hydrogel scaffold using high-performance liquid chromatography (HPLC). Poly(ethylene glycol) dimethacrylate (PEGDMA) hydrogel tablets were fabricated via photoinitiated crosslinking and subsequently loaded with model active pharmaceutical ingredients (APIs), namely, porcine insulin (PI), fluorescein isothiocyanate-labeled bovine serum albumin (FBSA), prednisone (PSE), or a combination of all three. The hydrogel tablets were placed into release chambers and sampled over 21 days, and APIs were quantified using the method described herein. Six compounds were isolated and quantified in total. Release kinetics based on chemical properties of the APIs did not give systematic relationships; however, PSE was found to have improved device loading versus PI and FBSA. Rapid analysis of three model APIs released from a PEGDMA CDDS was achieved with a direct, single-injection HPLC method. Development of CDDS platforms is posited to benefit from such analytical approaches, potentially affording innovative solutions to complex disease states.
*22535518* 22535518 Development and Characterization of Zein-Based Micro Carrier System for Sustained Delivery of Aceclofenac Sodium. AAPS PharmSciTech 2012; 13 (1): 143-9
Nonsteroidal anti-inflammatory drugs (NSAIDs) induce gastric injury on long-term usage. This study aims at reducing the side effect of NSAIDs by encapsulating in zein, an acid-resistant biopolymer. Aceclofenac-loaded zein microspheres were prepared by emulsification and solvent evaporation method. The stability of zein microspheres at gastric pH retarded the release of the entrapped drug and hence reduces the possibility of gastric injury. However, the in vitro release of aceclofenac was sustained up to 72 h at intestinal pH. Thus, zein microspheres pave the way for the development of safe and sustained delivery system for NSAIDs thereby achieving the desired therapeutic potential with reduced side effects for chronic inflammatory disorders.
*22167417* 22167417 In Vitro Characterization of Chitosan Gels for Buccal Delivery of Celecoxib: Influence of a Penetration Enhancer. AAPS PharmSciTech 2012; 13 (1): 101-11
Celecoxib (Cx) shows high efficacy in the treatment of osteoarthritis and rheumatoid arthritis as a result of its high specificity for COX-2, without gastrolesivity or interference with platelet function at therapeutic concentrations. Besides of anti-inflammatory effects, Cx also has a potential role for oral cancer chemoprevention. For these conditions, oral administration in long-term treatment is a concern due to its systemic side effects. However, local application at the site of injury (e.g., buccal inflammation conditions or chemoprevention of oral cancer) is a promising way to reduce its toxicity. In this study, the in vitro characterization of mucoadhesive chitosan (CHT) gels associated to Azone® was assessed to explore the potential buccal mucosal administration of Cx in this tissue. Rheological properties of gels were analyzed by a rheometer with cone-plate geometry. In vitro Cx release and permeability studies used artificial membranes and pig cheek mucosa, respectively. Mucoadhesion were measured with a universal test machine. CHT gels (3.0%) containing 2.0% or 3.0% Az showed more appropriate characteristics compared to the others: pH values, rheology, higher amount of Cx retained in the mucosa, and minimal permeation through mucosa, besides the highest mucoadhesion values, ideal for buccal application. Moreover, the flux (J) and amounts of drug released decreased with increased CHT and Az concentrations. CHT gels (3.0%) associated with 2.0% or 3.0% Az may be considered potential delivery systems for buccal administration of Cx.
*22160883* 22160883 Preparation and In Vitro/In Vivo Evaluation of Microparticle Formulations Containing Meloxicam. AAPS PharmSciTech 2012; 13 (1): 46-52
In this study, we have formulated chitosan-coated sodium alginate microparticles containing meloxicam (MLX) and aimed to investigate the correlation between in vitro release and in vivo absorbed percentages of meloxicam. The microparticle formulations were prepared by orifice ionic gelation method with two different sodium alginate concentrations, as 1% and 2% (w/v), in order to provide different release rates. Additionally, an oral solution containing 15 mg of meloxicam was administered as the reference solution for evaluation of in vitro/in vivo correlation (ivivc). Following in vitro characterization, plasma levels of MLX and pharmacokinetic parameters [elimination half-life (t1/2), maximum plasma concentration (Cmax), time for Cmax (tmax)] after oral administration to New Zealand rabbits were determined. Area under plasma concentration?time curve (AUC0??) was calculated by using trapezoidal method. A linear regression was investigated between released% (in vitro) and absorbed% (in vivo) with a model-independent deconvolution approach. As a result, increase in sodium alginate content lengthened in vitro release time and in vivo tmax value. In addition, for ivivc, linear regression equations with r2 values of 0.8563 and 0.9402 were obtained for microparticles containing 1% and 2% (w/v) sodium alginate, respectively. Lower prediction error for 2% sodium alginate formulations (7.419?±?4.068) compared to 1% sodium alginate formulations (9.458?±?5.106) indicated a more precise ivivc for 2% sodium alginate formulation.
*22101966* 22101966 Development and In Vitro/In Vivo Evaluation of Etodolac Controlled Porosity Osmotic Pump Tablets. AAPS PharmSciTech 2011; 12 (2): 485-95
The aim of the current work was the design and evaluation of etodolac controlled porosity osmotic pump (CPOP) tablets exhibiting zero-order release kinetics. Variables influencing the design of (1) core tablets viz., (a) osmogent type (sodium chloride, potassium chloride, mannitol, and fructose) and (b) drug/osmogent ratio (1:0.25, 1:0.50, and 1:0.75), and (2) CPOP tablets viz., (a) coating solution composition, (b) weight gain percentage (1?5%, w/w), and (c) pore former concentration (5%, 10%, and 20%, v/v), were investigated. Statistical analysis and kinetic modeling of drug release data were estimated. Fructose-containing core tablets showed significantly (P?0.05) more retarded drug release rates. An inverse correlation was observed between drug/fructose ratio and drug release rate. Coating of the optimum core tablets (F4) with a mixture of cellulose acetate solution (3%, w/v), diethyl phthalate, and polyethylene glycol 400 (85:10:5, v/v, respectively) till a 4% w/w weight gain enabled zero-order sustained drug delivery over 24 h. Scanning electron microscopy micrographs of coating membrane confirmed pore formation upon contact with dissolution medium. When compared to the commercial immediate-release Napilac® capsules, the optimum CPOP tablets (F4?34) provided enhanced bioavailability and extended duration of effective etodolac plasma concentration with minimum expected potential for side effects in healthy volunteers.
*21479749* 21479749 A Novel Injection-Molded Capsular Device for Oral Pulsatile Delivery Based on Swellable/Erodible Polymers. AAPS PharmSciTech 2011; 12 (1): 295-303
The feasibility of injection molding was explored in the preparation of a novel capsular device for oral pulsatile/delayed delivery based on swellable/erodible polymers. For this purpose, a mold intended to be coupled with a bench-top injection-molding press was designed. This was expected to enable the preparation of matching capsule cap and body items within a single manufacturing cycle and the selection of differing shell thicknesses (300, 600, and 900 ?m). Hydroxypropylcellulose (Klucel® EF, LF, and GF) was employed as the release-controlling polymer in admixture with polyethylene glycol 1500 (10%, w/w) as the plasticizer. After preliminary trials aimed at the setup of operating conditions, Klucel® EF and LF capsule shells with satisfactory technological properties were manufactured. The performance of capsular devices filled with a tracer drug powder was studied by means of a modified USP31 disintegration apparatus. Typical in vitro delayed release patterns were thereby obtained, with lag time increasing as a function of the wall thickness. A good correlation was found between the latter parameter and t10%, i.e., the time to 10% release, for both polymer grades employed. On the basis of the overall results, the investigated technique was proven suitable for the manufacturing of an innovative pulsatile release platform.
*21267684* 21267684 Polymeric Surfactant Based Etodolac Chewable Tablets: Formulation and In Vivo Evaluation. AAPS PharmSciTech 2010; 11 (4): 1730-7
Etodolac (ET) is a nonsteroidal anti-inflammatory drug with proved potential antitumor and uric acid lowering effects. It shows dissolution rate-dependent bioavailability. This work was carried out to improve the dissolution rate of etodolac using three carriers of known potential to improve solubility and hence dissolution rate of poorly soluble drugs through coevaporation technique. The polymeric surfactant inutec, 2-hydroxypropyl-?-cyclodextrin, and tromethamine were used at three different drug/carrier ratios. The dissolution rate of ET at pH 1.2 and 6.8 is improved in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. DSC of coevaporates at 1:5 drug/carrier ratio providing the fastest dissolution rate suggested loss of ET crystallinity which was further confirmed by X-ray diffraction. Inutec-based coevaporate was chosen for the formulation of ET chewable tablets. Chewable tablets (F3) that met the USP monograph specifications for ET tablets, with 86% dissolved amount within 15 min, was chosen for in vivo absorption study in comparison with pure ET-filled hard gelatin capsules. The results showed significantly higher mean Cmax and shorter mean Tmax (about 2 h earlier) and about 1.32-fold higher mean AUC0?24 values for the F3 chewable tablets compared to ET-filled capsules.
*21136309* 21136309 Design and In Vitro Evaluation of Capsaicin Transdermal Controlled Release Cubic Phase Gels. AAPS PharmSciTech 2010; 11 (3): 1405-10
The purpose of this study was to design and investigate the transdermal controlled release cubic phase gels containing capsaicin using glycerol monooleate (MO), propylene glycol (1,2-propanediol, PG), and water. Three types of cubic phase gels were designed based on the ternary phase diagram of the MO?PG?water system, and their internal structures were confirmed by polarizing light microscopy (PLM) and small-angle X-ray scattering (SAXS). Release results showed the cubic phase gels could provide a sustained system for capsaicin, while the initial water content in the gels was the major factor affecting the release rate. Release kinetics was determined to fit Higuchi?s square-root equation indicating that the release was under diffusion control. The calculated diffusion exponent showed the release from cubic phase gels was anomalous transport. The unique structure of the cubic phases, capsaicin distributed in the lipid bilayers, and cubic phase gel swelling contributed to the release mechanism. The cubic phase gel may be an interesting application for transdermal delivery system of capsaicin in alleviating the post-incision pain.
*20839080* 20839080 Chitosan/Polyethylene Glycol Beads Crosslinked with Tripolyphosphate and Glutaraldehyde for Gastrointestinal Drug Delivery. AAPS PharmSciTech 2010; 11 (3): 1128-37
This study reports on the preparation of chitosan (CS)/polyethylene glycol (PEG) hydrogel beads using sodium diclofenac (DFNa) as a model drug. Following the optimization of the polymer to drug ratio, the chitosan beads were modified by ionic crosslinking with sodium tripolyphosphate (TPP). The CS/PEG/DFNa beads obtained from a (w/w/w) ratio of 1/0.5/0.5 with crosslinking in 10% (w/v) TPP at pH 6.0 for 30 min yielded excellent DFNa encapsulation levels with over 90% loading efficiency. The dissolution profile of DFNa from CS/PEG/DFNa beads demonstrated that this formulation was able to maintain a prolonged drug release for approximately 8 h. Among the formulations tested, the CS/PEG/DFNa (1/0.5/1 (w/w/w)) beads crosslinked with a combination of TPP (10% (w/v) for 30 min) and glutaraldehyde (GD) (5% (w/v)) were able to provide minimal DFNa release in the gastric and duodenal simulated fluids (pH 1.2 and 6.8, respectively) allowing for a principally gradual drug release over 24 h in the intestinal (jejunum and ileum) simulated fluid (pH 7.4). Thus, overall the CS/PEG beads crosslinked with TPP and GD look to be a promising and novel alternative gastrointestinal drug release system.
*20652459* 20652459 Prednisolone-Loaded PLGA Microspheres. In Vitro Characterization and In Vivo Application in Adjuvant-Induced Arthritis in Mice. AAPS PharmSciTech 2010; 11 (2): 859-69
This study aimed at preparation of a sustained-release steroidal treatment for chronic inflammatory conditions, such as rheumatoid arthritis. To achieve such a goal, biodegradable poly-lactide-co-glycolide prednisolone-loaded microspheres were prepared using o/w emulsion solvent evaporation method. Formulation parameters were adjusted so as to optimize the microsphere characteristics. The prepared microspheres exhibited smooth and intact surfaces, with average size range not exceeding 65 µm. The encapsulation efficiency percent of most microsphere formulations fell within the range of 25?68%. Drug release from these microspheres took place over 4 weeks, with near-to-zero-order patterns. Two successful formulations were chosen for the treatment of unilateral arthritis, induced in mice using Freund s complete adjuvant (FCA). Inflammatory signs of adjuvant arthritis included severe swelling of the FCA-injected limbs, in addition to many histopathological lesions. These included inflammatory cell infiltration, synovial hyperplasia, cartilage, and bone erosion. Parenteral administration of the selected formulae dramatically reduced the swelling of the FCA-injected limbs. In addition, histological examination revealed that the microsphere treatment protocol efficiently protected cartilages and bones of mice, injected with FCA initial and booster doses, from erosion. These results could not be achieved by a single prednisolone dose of 5 mg/kg.
*20490959* 20490959 Negative Thermo-responsive Microspheres Based on Hydrolyzed Gelatin as Drug Delivery Device. AAPS PharmSciTech 2010; 11 (2): 652-62
This paper deals with the synthesis of thermo-responsive microspheres with proteic structure exhibiting a transition temperature close to the body temperature. Temperature-sensitive hydrogels have attracted extensive interest due to their potential and promising applications in drug delivery field since they can undergo a rapid and reversible phase transition from a swollen to a shrunken state depending on environmental temperature. The hydrogels were synthesized by free-radical polymerization of hydrolyzed methacrylated gelatin (HGel-MA) and N,N?-methylenebisacrylamide as pro-hydrophilic multifunctional macromer and crosslinker, respectively, and N-isopropylacrylamide as thermo-responsive monomer. Thermal analyses showed negative thermo-responsive behavior for all compositions and, by increasing the content of the hydrophilic moieties in the network, the transition temperature raised to 36.9°C, close to the physiological values. In order to test the materials as drug carriers, diclofenac sodium salt was chosen as model drug. Drug release profiles, in phosphate buffer solution (pH 7.0, 10?3 M) at 25 and 40°C, depend on the hydrogel?s crosslinking degree and hydrophilic/hydrophobic balance in the polymeric network. For all formulations, in the shrunken state, the drug release percent values ranged from 80% to 100% after 24 h, and after 3 h, more than 60% of therapeutics was delivered. On the contrary, the swelling of the loaded microparticles produces, even after 30 h, a drug release percent of about 75%. By using semi-empirical equations, the release mechanism was extensively studied and the diffusional contribute was evaluated. The physico-chemical characteristics of thermo-responsive materials confirm the applicability of the microspheres as drug delivery device.
*20405255* 20405255 A Novel Transdermal Delivery System for the Anti-Inflammatory Lumiracoxib: Influence of Oleic Acid on In Vitro Percutaneous Absorption and In Vivo Potential Cutaneous Irritation. AAPS PharmSciTech 2010; 11 (2): 621-9
Transdermal delivery of non-steroidal anti-inflammatory drugs may be an interesting strategy for delivering these drugs to the diseased site, but it would be ineffective due to low skin permeability. We investigated whether oleic acid (OA), a lipid penetration enhancer in poloxamer gels named poloxamer-based delivery systems (PBDS), can improve lumiracoxib (LM) delivery to/through the skin. The LM partition coefficient (K) studies were carried out in order to evaluate the drug lipophilicity grade (Koctanol/buffer), showing values >1 which demonstrated its high lipophilicity. Both in vitro percutaneous absorption and skin retention studies of LM were measured in the presence or absence of OA (in different concentrations) in PBDS using porcine ear skin. The flux of in vitro percutaneous absorption and in vitro retention of LM in viable epidermis increased in the presence of 10.0% (w/w) OA in 25.0% (w/w) poloxamer gel. In vivo cutaneous irritation potential was carried out in rabbits showing that this formulation did not provide primary or cumulative cutaneous irritability in animal model. The results showed that 25.0% poloxamer gel containing 10.0% OA is potential transdermal delivery system for LM.
*20373151* 20373151 Development and Characterization of Enteric-Coated Immediate-Release Pellets of Aceclofenac by Extrusion/Spheronization Technique Using ?-Carrageenan as a Pelletizing Agent. AAPS PharmSciTech 2010; 11 (1): 336-43
In the present study, an attempt was made to prepare immediate-release enteric-coated pellets of aceclofenac, a poorly soluble nonsteroidal anti-inflammatory drug that has a gastrointestinal intolerance as its serious side effect. Formulation of enteric-coated pellets with improved solubility of aceclofenac could address both of these problems. To achieve these goals, pellets were prepared by extrusion?spheronization method using pelletizing agents that can contribute to the faster disintegration and thereby improve the solubility of the drug. Different disintegrants like ?-cyclodextrin, kollidon CL, Ac-Di-Sol, and sodium starch glycolate were tried in order to further improve disintegration time. The pellets were characterized for drug content, particle size distribution, flow properties, infrared spectroscopy, surface morphology, disintegration rate, and dissolution profile. The formulations, which showed best disintegration and dissolution profiles, were coated with Eudragit L100-55, an enteric-coated polymer which does not dissolve at gastric pH but dissolves at intestinal pH, releasing the drug immediately in the dissolution medium. The optimized enteric-coated formulation containing 20% ?-carrageenan, lactose, and sodium starch glycolate as a disintegrant did inhibit the release of the drug for 2 h in 0.1 N HCl, whereas 87% of the drug was released within 45 min. The improvement was substantial when it was compared with solubility of pure drug under the same conditions. Thus, dissolution profiles suggested that combination of ?-carrageenan and sodium starch glycolate resulted into fast-disintegrating, immediate-release pellets, overcoming the bioavailability problem of the poorly soluble drug, aceclofenac, and enteric coating of these pellets avoids the exposure of aceclofenac to ulcer-prone areas of the gastrointestinal tract.
*20195805* 20195805 Ketoprofen Absorption by Muscle and Tendon after Topical or Oral Administration in Patients Undergoing Anterior Cruciate Ligament Reconstruction. AAPS PharmSciTech 2010; 11 (1): 154-8
Topical ketoprofen patches are widely used in the treatment of musculoskeletal pain, but the pharmacokinetics of ketoprofen following topical application remain unclear. This open-label, single-dose pharmacokinetic study was designed to determine the concentrations of ketoprofen in the semitendinosus muscle/tendon and plasma after topical application or oral administration to patients scheduled for anterior cruciate ligament reconstruction. Two ketoprofen patches (20 mg each) were applied over the semitendinosus muscle/tendon for 1, 6, 14, or 20 h before surgery in 21 patients, while one sustained-release 150 mg ketoprofen capsule was administered to six patients 14 h before surgery. Ten untreated patients served as the control group. The main outcome measures were the semitendinosus muscle/tendon and plasma concentrations of ketoprofen at 1, 6, 14, and 20 h. Ketoprofen was detected in the semitendinosus muscle/tendon from about 1 h after topical application. The peak concentration was reached at 6 h, and it decreased gradually until 20 h, although the concentration at 20 h was still higher than that at 1 h. Unlike the tissue concentration, the plasma concentration of ketoprofen increased gradually after topical application. At 14 h, there was no significant difference of the tissue concentration between the topical and oral groups, although the plasma concentration was about 17-fold higher in the oral group than in the topical group. In conclusion, following topical application in a patch, ketoprofen shows rapid and sustained delivery to the underlying tissues without a significant increase of the plasma drug concentration.
*20087696* 20087696 In Vitro and In Vivo Evaluation of Proniosomes Containing Celecoxib for Oral Administration. AAPS PharmSciTech 2010; 11 (1): 85-9
The objectives of this research were to prepare celecoxib proniosomes and evaluate the influence of proniosomal formulation on the oral bioavailability of the drug in human volunteers. A new proniosomal delivery system for a poorly water-soluble drug such as celecoxib was developed and subjected to in vitro and in vivo studies. Proniosomes were prepared by sequential spraying method, which consisted of cholesterol, span 60, and dicetyl phosphate in a molar ratio of 1:1: 0.1, respectively. The average entrapment percent of celecoxib proniosome-derived niosomes was about 95%. The prepared proniosomes showed marked enhancement in the dissolution of celecoxib as compared to pure drug powder. The bioavailability of 200 mg single dose of both celecoxib proniosomal formulation and a conventional marketed celecoxib capsule was studied in human volunteers. The obtained results show that the proniosomal formulation significantly improved the extent of celecoxib absorption than conventional capsule. The mean relative bioavailability of the proniosomal formulation to the conventional capsule was 172.06?±?0.14%. The mean Tmax for celecoxib was prolonged when given as proniosomal capsule. There was no significant difference between the values of Kel and t1/2 for both celecoxib preparations. In conclusion, the proniosomal oral delivery system of celecoxib with improved bioavailability was established.
*20058106* 20058106 Design and In Vitro Evaluation of Novel Sustained-Release Double-Layer Tablets of Lornoxicam: Utility of Cyclodextrin and Xanthan Gum Combination. AAPS PharmSciTech 2009; 10 (4): ä
The objective of the present study was to develop new directly compressed, double-layer tablets (DLTs) of lornoxicam, a highly potent nonsteroidal anti-inflammatory drug with short half-life, that are characterized by initial burst drug release in the stomach and comply with the release requirements of sustained-release products. Each of the proposed DLTs is composed of a fast-release layer and a sustained-release layer, anticipating rapid drug release that starts in the stomach to rapidly alleviate the symptoms and continues in the intestine to maintain protracted analgesic effect. An amorphous, freeze-dried inclusion complex of lornoxicam with hydroxypropyl-?-cyclodextrin, present in 1:2 (drug/cyclodextrin) molar ratio, was employed in the fast-release layer to enhance the dissolution of lornoxicam in the stomach and assure rapid onset of its analgesic effect. Xanthan gum (XG), a hydrophilic matrix-forming agent, was integrated in the sustained-release layer to provide appropriate sustainment of drug release. The weight ratios between the sustained-release layer and fast-release layer present in DLTs were adjusted to reach optimal formulations. DLTs composed of sustained-release layer (40% XG) to fast-release layer in 2:1 weight ratio and those composed of sustained-release layer (50% XG) to fast-release layer in 1:1 weight ratio showed the desired release profile. The drug contained in the fast-release layer showed an initial burst drug release of more than 30% of its drug content during the first 30 min of the release study followed by gradual release of the drug for a period of 8 h.
*19921543* 19921543 Microemulsion System with Improved Loading of Piroxicam: A Study of Microstructure. AAPS PharmSciTech 2009; 10 (4): ä
Formulation of a new oil-in-water (o/w) microemulsion composed of castor oil/Tween 80/ethanol/phosphate buffer for enhancing the loading capacity of an anti-inflammatory drug piroxicam has been accomplished. The pseudo-ternary phase diagram has been delineated at constant surfactant/cosurfactant ratio (1:2). The internal structure of so created four-component system was elucidated by means of an analysis of isotropic area magnitudes in the phase diagram. Conductivity (?), kinematic viscosity (k?), and surface tension (?) studies with the variation in ?w (weight fraction of aqueous phase) show the occurrence of structural changes from water-in-oil (w/o) microemulsion to oil-in-water (o/w). Along with the solubility and partition studies of piroxicam in microemulsion components, the changes in the microstructure of the microemulsion after incorporation of drug have been evaluated using pH, ?, ?, k?, and density studies. Piroxicam, a poorly water-soluble drug displayed high solubility (1.0%) in an optimum microemulsion formulation using ethanol (55.0%), Tween 80 (26.5%), castor oil (7.5%), and phosphate buffer (11.0%). The results have shown that the microemulsion remained stable after the incorporation of piroxicam. Fluorescence spectra analysis taking pyrene as fluorescent probe was performed, and the results showed that pyrene was completely solubilized in the oil phases of the bicontinuous microemulsions. The fluorescence spectrum of the model drug piroxicam was used to probe the intramicellar region of nonionic microemulsion. The results showed that the piroxicam was localized in the interfacial film of microemulsion systems more deeply in the palisade layer with ethanol as the cosurfactant.
*19876741* 19876741 Kneading Technique for Preparation of Binary Solid Dispersion of Meloxicam with Poloxamer 188. AAPS PharmSciTech 2009; 10 (4): 1206-15
The aim of the present study was to enhance the dissolution rate of meloxicam (MLX), a practically water-insoluble drug by preparation of solid dispersion using a hydrophilic polymer, poloxamer 188 (PXM). The kneading technique was used to prepare solid dispersions. A 32 full factorial design approach was used for optimization wherein the drug, polymer ratio (X1), and the kneading time (X2) were selected as independent variables and the dissolution efficiency at 60 min (%DE60) and yield percent were selected as the dependent variable. Multiple linear regression analysis revealed that for obtaining higher dissolution of MLX from PXM solid dispersions, a high level of X1 and a high level of X2 were suitable. The use of a factorial design approach helped in optimization of the preparation and formulation of solid dispersion. The optimized formula was characterized by solubility studies, angle of repose, and contact angle; Fourier transform infrared spectroscopy, differential scanning calorimetry, x-ray diffraction studies, and scanning electron microscopy demonstrated that enhanced dissolution of MLX from solid dispersion might be due to a decrease in the crystallinity of MLX and PXM. Analysis of dissolution data of optimized formula indicated the best fitting with Korsemeyer?Peppas model and the drug release kinetics as Fickian diffusion. In conclusion, dissolution enhancement of MLX was obtained by preparing its solid dispersion with PXM using kneading technique.
*19862626* 19862626 Microcapsules and Transdermal Patch: A Comparative Approach for Improved Delivery of Antidiabetic Drug. AAPS PharmSciTech 2009; 10 (3): 928-34
Glibenclamide (GL)-loaded microcapsules (MC) and transdermal patches (TDP) were formulated and in vitro and in vivo parameters compared to find out the best route of drug administration. The formulation TDP1 having a drug?polymer ratio 1:1 showed comparatively higher GL release and better permeation across mice skin (p?0.05). From the comparative study, it was concluded that the transdermal system of GL produced better improvement compared to oral microcapsule administration (p?0.05). The transdermal system exhibited comparatively slow and continuous supply of GL at a desired rate to systemic circulation avoiding metabolism, which improved day-to-day glycemic control in diabetic subjects. Transdermal system of GL exhibited better control of hyperglycemia and prolonged plasma half-life by transdermal systems (9.6?±?1.2 h) in comparison with oral microcapsule (5.84?±?2.1 h), indicating that the drug, when administered by transdermal systems, will remain in the body for a longer period. From the glucose tolerance test, transdermal route effectively maintained the normoglycemic levels in contrast to the oral group (MC1), which produced remarkable hypoglycemia ranging from ?12.6?±?2.1% to ?18?±?2.3%. The significantly high (p?0.05) area under the curve values observed with transdermal system (1,346.2?±?92.3 ng ml?1 h?1) also indicate increased bioavailability of the drug from these systems compared to the oral route (829.8?±?76.4 ng ml?1 h?1).
*19629706* 19629706 Stability Studies of Microparticulate System with Piroxicam as Model Drug. AAPS PharmSciTech 2009; 10 (3): ä *19568938* 19568938 Colon Specific Delivery of Indomethacin: Effect of Incorporating pH Sensitive Polymers in Xanthan Gum Matrix Bases. AAPS PharmSciTech 2009; 10 (2): 418-29
In the present study, an attempt has been made to design controlled release colon-specific formulations of indomethacin by employing pH responsive polymers Eudragit (L100 or S100) in matrix bases comprised of xanthan gum. The prepared tablets were found to be of acceptable quality with low-weight variation and uniform drug content. In vitro release studies indicated rapid swelling and release of significant percentage of drug in the initial period from matrix tablets composed of xanthan gum alone. Addition of pH responsive polymers Eudragit (L100 or S100) to xanthan gum matrix resulted in negligible to very low drug release in the initial period in acidic to weakly acidic medium. Furthermore, with increase in pH of the dissolution medium due to dissolution of Eudragit L100/Eudragit S100 that resulted in the formation of a porous matrix, faster but controlled drug release pattern was observed. Thus, a sigmoidal release pattern was observed from the designed formulations suitable for colonic delivery. Drug release mechanism in all cases was found to be of super case II type, indicating erosion to be the primary cause of drug release. Since the drug release from almost all the matrix bases in the initial phase was negligibly low and followed with controlled release for about 14?16 h, it was concluded that a matrix design of this composition could have potential applications as a colon-specific drug delivery device with additional advantage of easy scale-up and avoidance of all-or-none phenomenon associated with coated colon-specific systems.
*19381832* 19381832 Mechanistic Evaluation of the Effect of Sintering on Compritol® 888 ATO Matrices. AAPS PharmSciTech 2009; 10 (2): 355-60
The present research studied the effect of sintering technique in the development of a controlled release formulation for ketorolac tromethamine. The method consisted of mixing drug and wax powder (Compritol® 888 ATO) along with lactose as diluent and talc as lubricant followed by direct compression at room temperature. The compressed fluffy matrices were kept at 80°C for 1, 2, and 3 h for sintering. The sintered tablets were characterized by their physical parameters and in vitro dissolution profile. The sintering time markedly affected the drug release properties of Compritol® 888 ATO matrices. It is notable that the release rate of ketorolac tromethamine from matrices was inversely related to the time of sintering. This may be due to the increase in the extent and firmness of sintering which further compacts the mass so that drug release is affected. Contact angle measurement and scanning electron microscopy analysis indicated that heat treatment caused the wax to melt and redistribute. This redistributed wax formed a network-like structure in which the drug along with lactose is entrapped. This particular formed matrix is responsible for retarding the drug release. Fourier transform infrared spectroscopy results did not show any drug?wax interaction due to sintering. Differential scanning calorimetric and powder X-ray diffraction studies ruled out the occurrence of solid solution and polymorphic changes of the drug. Drug release from the wax tablets with or without sintering was best described by the Higuchi equation.
*19333763* 19333763 Studies on Mefenamic Acid Microparticles: Formulation, In Vitro Release, and In Situ Studies in Rats. AAPS PharmSciTech 2009; 10 (1): 104-12
In this study, we investigated the in vitro characteristics of mefenamic acid (MA) microparticles as well as their effects on DNA damage. MA-loaded chitosan and alginate beads were prepared by the ionotropic gelation process. Microsponges containing MA and Eudragit RS 100 were prepared by quasi-emulsion solvent diffusion method. The microparticles were characterized in terms of particle size, surface morphology, encapsulation efficiency, and in vitro release profiles. Most of the formulation variables manifested an influence on the physical characteristics of the microparticles at varying degrees. We also studied the effects of MA, MA-loaded microparticles, and three different polymers on rat brain cortex DNA damage. Our results showed that DNA damage was higher in MA-loaded Eudragit microsponges than MA-loaded biodegradable chitosan or alginate microparticles.
*19184450* 19184450 Formulation of Sustained-Release Dosage Form of Verapamil Hydrochloride by Solid Dispersion Technique Using Eudragit RLPO or Kollidon®SR. AAPS PharmSciTech 2009; 10 (1): 27-33
The release of verapamil hydrochloride from tablets with Eudragit RLPO or Kollidon®SR with different drug-to-polymer ratios were investigated with a view to develop twice-daily sustained-release dosage form by solid dispersion (SD) technique. The SDs containing Eudragit RLPO or Kollidon®SR at drug-polymer ratios of 1:1, 1:2, and 1:3 with verapamil hydrochloride were developed using solvent evaporation technique. The physical mixtures of drug and both polymers were prepared by using simple mixing technique at the same ratio as solid dispersion. The physicochemical properties of solid dispersion were evaluated by using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). The study of DSC, XRD, and FTIR could not show significant interaction between verapamil HCl and Kollidon®SR or Eudragit RLPO. The solid dispersions or physical mixtures were compressed to tablets. The tablets were prepared with solid dispersions containing Eudragit RLPO or Kollidon®SR, with all the official requirements of tablet dosage forms fulfilled. Tablets prepared were evaluated for the release of verapamil hydrochloride over a period of 12 h in pH 6.8 phosphate buffer using US Pharmacopoeia type II dissolution apparatus. The in vitro drug release study revealed that the tablet containing Eudragit has extended the release rate for 12 h whereas the tablet containing Kollidon®SR at the same concentration has extended the release rate up to 8 h. The in vitro release profile and the mathematical models indicate that release of verapamil hydrochloride can be effectively controlled from a tablet containing solid dispersions of Eudragit RLPO. The reduction of size fraction of the SD system from 200?250 to 75?125 ?m had a great effect on the drug release.
*19145487* 19145487 Beyond PubMed : called unfree