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10.1007/s40262-020-00933-8 http://scihub22266oqcxt.onion/10.1007/s40262-020-00933-8 32856282!7453069!32856282     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Clin+Pharmacokinet 2020 ; 59 (10): 1251-1260 Nephropedia Template TP {{tp|p=32856282|t=2020. Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs HIV Patients: The Role of Interleukin-6 |pdf=|usr=}}{{32856282}} gab.com Text Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs HIV Patients: The Role of Interleukin-6 JO: Clin Pharmacokinet http://www.kidney.de/pget.php?&tw=1&pmid=32856282 #FOAvip BACKGROUND: Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. OBJECTIVE: The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. METHODS: Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. RESULTS: A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (V(d)), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p < 0.001). CART analysis found that an IL-6 level of 18 pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean +/- standard deviation 3.47 +/- 1.90 vs. 8.03 +/- 3.24 L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels >/= 18 pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18 pg/mL or HIV patients (2.78 [2.16-4.47] vs. 7.24 [5.88-10.38] vs. 9.75 [8.45-13.79] L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP) 3A4-mediated metabolism of darunavir. CONCLUSIONS: This is a proof-of-concept of SARS-CoV-2 disease-drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients. Twit Text FOAVip Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs HIV Patients: The Role of Interleukin-6 ????Clin Pharmacokinet http://www.kidney.de/pget.php?&tw=1&pmid=32856282 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=32856282 #FOAvip English Wikipedia <ref>{{Cite pmid|32856282}}</ref> Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs HIV Patients: The Role of Interleukin-6 #MMPMID32856282 Cojutti PG; Londero A; Della Siega P; Givone F; Fabris M; Biasizzo J; Tascini C; Pea F Clin Pharmacokinet 2020[Oct]; 59 (10): 1251-1260 PMID32856282show ga BACKGROUND: Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. OBJECTIVE: The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. METHODS: Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. RESULTS: A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (V(d)), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p < 0.001). CART analysis found that an IL-6 level of 18 pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean +/- standard deviation 3.47 +/- 1.90 vs. 8.03 +/- 3.24 L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels >/= 18 pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18 pg/mL or HIV patients (2.78 [2.16-4.47] vs. 7.24 [5.88-10.38] vs. 9.75 [8.45-13.79] L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP) 3A4-mediated metabolism of darunavir. CONCLUSIONS: This is a proof-of-concept of SARS-CoV-2 disease-drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients. |Adult[MESH] |Age Factors[MESH] |Aged[MESH] |Betacoronavirus[MESH] |Body Weights and Measures[MESH] |COVID-19[MESH] |Comorbidity[MESH] |Coronavirus Infections/*drug therapy[MESH] |Cytochrome P-450 CYP3A[MESH] |Darunavir/*pharmacokinetics/therapeutic use[MESH] |Dose-Response Relationship, Drug[MESH] |Female[MESH] |HIV Infections/*drug therapy[MESH] |HIV Protease Inhibitors/*pharmacokinetics/therapeutic use[MESH] |Humans[MESH] |Interleukin-6/*blood[MESH] |Male[MESH] |Metabolic Clearance Rate[MESH] |Middle Aged[MESH] |Models, Biological[MESH] |Monte Carlo Method[MESH] |Pandemics[MESH] |Pneumonia, Viral/*drug therapy[MESH] |Retrospective Studies[MESH] |SARS-CoV-2[MESH]Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Pat(epmc).pdf DeepDyve Pubget Overpricing