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10.1007/s00228-017-2205-7 http://scihub22266oqcxt.onion/10.1007/s00228-017-2205-7 C5384962!5384962 !28160012     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28160012 &cmd=llinks): Failed to open stream: HTTP request failed! 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First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3K? inhibitor for the treatment of immune and inflammatory diseases |pdf=|usr=}}{{28160012 }} gab.com Text First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3K inhibitor for the treatment of immune and inflammatory diseases JO: Eur J Clin Pharmacol http://www.kidney.de/pget.php?&tw=1&pmid=28160012 #FOAvip PURPOSE: PI3Ks are potential therapeutic targets in immune-inflammatory diseases. These studies aimed to investigate the safety, tolerability and PK profile of seletalisib, a selective inhibitor of PI3K? in humans. METHODS: These phase I, randomised, double-blind, placebo-controlled, single-centre studies (NCT02303509, NCT02207595) evaluated single and multiple oral doses of seletalisib (5-90 mg QD and 30 mg BID) in healthy adults and subjects with mild-to-moderate psoriasis (Study-1). Pharmacodynamic effects on markers of inflammation were assessed via changes in ex vivo basophil degranulation and histological assessment of psoriatic skin biopsies. RESULTS: Seletalisib was well tolerated at doses ?15 mg (Study-1) and ?45 mg QD (Study-2) for 14 days. No safety concerns or dose-limiting toxicities were identified (Study-1). Incidence of gastrointestinal-related AEs was not dose related but higher incidences of rash AEs were associated with higher-dose seletalisib (Study-2 rash AEs: 18 in 12 seletalisib-treated subjects versus 1 in 1 placebo-treated subject). Mean seletalisib plasma concentration-time profiles increased with increasing doses after single and multiple dosing, with no major deviations from dose-proportionality. There was no unexpected accumulation or loss of exposure after multiple dosing (time-independent pharmacokinetic profile). Apparent t (1/2) values were supportive of once-daily dosing (geometric mean t(1/2): Study-1, 17.7-21.1 h; Study-2, 18.1-22.4 h). No clinically significant food effect was observed (Study-1). Pharmacodynamic findings demonstrated ex vivo inhibition of basophil degranulation, improvements in histological assessment of skin biopsies and other markers of psoriatic biology and preliminary evidence of target engagement in psoriatic skin tissue. CONCLUSIONS: Seletalisib safety, tolerability and pharmacokinetic/pharmacodynamic profiles support its continued clinical development in immune-inflammatory diseases. Twit Text FOAVip First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3K inhibitor for the treatment of immune and inflammatory diseases ????Eur J Clin Pharmacol http://www.kidney.de/pget.php?&tw=1&pmid=28160012 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28160012 #FOAvip English Wikipedia <ref>{{Cite pmid|28160012 }}</ref> First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3K? inhibitor for the treatment of immune and inflammatory diseases #MMPMID28160012 Helmer E ; Watling M ; Jones E ; Tytgat D ; Jones M ; Allen R ; Payne A ; Koch A ; Healy E Eur J Clin Pharmacol 2017[May]; 73 (5 ): 581-591 PMID28160012 show ga PURPOSE: PI3Ks are potential therapeutic targets in immune-inflammatory diseases. These studies aimed to investigate the safety, tolerability and PK profile of seletalisib, a selective inhibitor of PI3K? in humans. METHODS: These phase I, randomised, double-blind, placebo-controlled, single-centre studies (NCT02303509, NCT02207595) evaluated single and multiple oral doses of seletalisib (5-90 mg QD and 30 mg BID) in healthy adults and subjects with mild-to-moderate psoriasis (Study-1). Pharmacodynamic effects on markers of inflammation were assessed via changes in ex vivo basophil degranulation and histological assessment of psoriatic skin biopsies. RESULTS: Seletalisib was well tolerated at doses ?15 mg (Study-1) and ?45 mg QD (Study-2) for 14 days. No safety concerns or dose-limiting toxicities were identified (Study-1). Incidence of gastrointestinal-related AEs was not dose related but higher incidences of rash AEs were associated with higher-dose seletalisib (Study-2 rash AEs: 18 in 12 seletalisib-treated subjects versus 1 in 1 placebo-treated subject). Mean seletalisib plasma concentration-time profiles increased with increasing doses after single and multiple dosing, with no major deviations from dose-proportionality. There was no unexpected accumulation or loss of exposure after multiple dosing (time-independent pharmacokinetic profile). Apparent t (1/2) values were supportive of once-daily dosing (geometric mean t(1/2): Study-1, 17.7-21.1 h; Study-2, 18.1-22.4 h). No clinically significant food effect was observed (Study-1). Pharmacodynamic findings demonstrated ex vivo inhibition of basophil degranulation, improvements in histological assessment of skin biopsies and other markers of psoriatic biology and preliminary evidence of target engagement in psoriatic skin tissue. CONCLUSIONS: Seletalisib safety, tolerability and pharmacokinetic/pharmacodynamic profiles support its continued clinical development in immune-inflammatory diseases. |*Phosphoinositide-3 Kinase Inhibitors [MESH] |Administration, Oral [MESH] |Biological Availability [MESH] |Double-Blind Method [MESH] |Enzyme Inhibitors/administration & dosage/adverse effects/*therapeutic use [MESH] |Humans [MESH] |Placebos [MESH] |Psoriasis/*drug therapy [MESH] |Pyridines/administration & dosage/*therapeutic use [MESH]First-in-human studies of seletalisib, an orally bioavailable small-mo(epmc).pdf DeepDyve Pubget Overpricing