{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T19:15:38Z","timestamp":1780514138421,"version":"3.54.1"},"reference-count":50,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>ACT\u20101014\u20106470 is an orally available complement factor 5a receptor 1 antagonist and a novel treatment option in auto\u2010inflammatory diseases. The in vitro inhibition potential of ACT\u20101014\u20106470 on cytochrome P450 isozymes (CYPs) and its effect on the pharmacokinetics (PK) of the CYP2C19 and CYP3A4 substrates omeprazole and midazolam, respectively, in humans were assessed. In vitro assays were conducted with isoform\u2010specific substrates in human liver microsomes. In an open\u2010label, two\u2010period, fixed\u2010sequence cocktail study, single doses of 20\u2009mg omeprazole and 2\u2009mg midazolam were administered concomitantly to 20 healthy male subjects alone (treatment A) and after a single dose of 100\u2009mg ACT\u20101014\u20106470 (treatment B) under fed conditions. Safety and PK assessments were performed. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of noncompartmental PK parameters of treatment B versus treatment A were calculated. In vitro, no time\u2010dependent inhibition was observed and the lowest inhibition constant of 4.3\u2009\u03bcM ACT\u20101014\u20106470 was recorded for CYP2C19. In humans, GMRs (90% CI) of omeprazole PK were 1.9 (1.5\u20132.5) for maximum plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) and 1.9 (1.5\u20132.3) for area under the plasma concentration\u2010time curve from 0 to 12\u2009h (AUC<jats:sub>0\u201012 h<\/jats:sub>). Midazolam PK showed GMRs (90% CI) of 1.1 (1.1\u20131.2) for <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> and 1.5 (1.4\u20131.6) for AUC<jats:sub>0\u201024\u2009h<\/jats:sub>. All treatments were well\u2010tolerated. In line with in vitro results and regulatory risk factor calculation, the increased exposure to omeprazole and midazolam in humans after concomitant administration with a single dose of 100\u2009mg ACT\u20101014\u20106470 reflected a weak inhibition of CYP2C19 and CYP3A4.<\/jats:p>","DOI":"10.1111\/cts.13525","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T07:14:29Z","timestamp":1681283669000},"page":"1220-1231","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evaluation of the cytochrome <scp>P450 2C19<\/scp> and <scp>3A4<\/scp> inhibition potential of the complement factor 5a receptor 1 antagonist <scp>ACT<\/scp>\u20101014\u20106470 in vitro and in vivo"],"prefix":"10.1111","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9308-5853","authenticated-orcid":false,"given":"Marion","family":"Anliker\u2010Ort","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"},{"name":"Pediatric Pharmacology and Pharmacometrics University Children's Hospital Basel (UKBB), University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-5817","authenticated-orcid":false,"given":"Jasper","family":"Dingemanse","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephane","family":"Delahaye","sequence":"additional","affiliation":[{"name":"Department of Preclinical Drug Metabolism and Pharmacokinetics Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubo\u0161","family":"Jan\u016f","sequence":"additional","affiliation":[{"name":"CEPHA s.r.o.  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