{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T03:55:24Z","timestamp":1769572524136,"version":"3.49.0"},"reference-count":32,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T00:00:00Z","timestamp":1693785600000},"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":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The orally available anti\u2010hepatitis C virus (HCV) drug simeprevir exhibits nonlinear pharmacokinetics at the clinical doses due to saturation of cytochrome P450 (CYP) 3A4 metabolism and organic anion transporting peptide (OATP) 1B mediated hepatic uptake. Additionally, simeprevir increases exposures of concomitant drugs by CYP3A4 and OATP1B inhibition. The objective of this study was to develop physiologically\u2010based pharmacokinetic (PBPK) models that could describe drug\u2013drug interactions (DDIs) of simeprevir with concomitant drugs via CYP3A4 and OATP1B inhibition, and also to capture the effects on coproporphyrin\u2010I (CP\u2010I), an endogenous biomarker of OATP1B. PBPK modeling estimated unbound simeprevir inhibitory constant (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>) of 2.89\u2009\u03bcM against CYP3A4 in the DDI results between simeprevir and midazolam in healthy volunteers. Then, we analyzed the DDIs between simeprevir and atorvastatin, a dual substrate of CYP3A4 and OATP1B, in healthy volunteers, and unbound <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> against OATP1B was estimated to be 0.00347\u2009\u03bcM. Finally, we analyzed the increase in the blood level of CP\u2010I by simeprevir to verify the <jats:italic>K<\/jats:italic><jats:sub>i,OATP1B<\/jats:sub>. Because CP\u2010I was measured in subjects with HCV with various hepatic fibrosis state, Monte Carlo simulation was performed to involve the decreases in expression levels of hepatic CYP3A4 and OATP1B and their interindividual variabilities. The PBPK modeling coupled with Monte Carlo simulation using the <jats:italic>K<\/jats:italic><jats:sub>i,OATP1B<\/jats:sub> value obtained from atorvastatin study reasonably recovered the observed relationship between CP\u2010I and simeprevir blood levels. In conclusion, the simeprevir PBPK model developed in this study can quantitatively describe the increase in exposures of concomitant drugs and an endogenous biomarker via inhibition of CYP3A4 and OATP1B.<\/jats:p>","DOI":"10.1002\/psp4.13023","type":"journal-article","created":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T05:44:55Z","timestamp":1693892695000},"page":"1461-1472","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Physiologically\u2010based pharmacokinetic modeling for investigating the effect of simeprevir on concomitant drugs and an endogenous biomarker of OATP1B"],"prefix":"10.1002","volume":"12","author":[{"given":"Shinji","family":"Nakayama","sequence":"first","affiliation":[{"name":"DMPK Research Laboratories, Shoyaku, Innovative Research Division Mitsubishi Tanabe Pharma Corporation  Yokohama Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kota","family":"Toshimoto","sequence":"additional","affiliation":[{"name":"Systems Pharmacology, Non\u2010Clinical Biomedical Science, Applied Research and Operations Astellas Pharma Inc.  Ibaraki Japan"},{"name":"Sugiyama Laboratory, RIKEN Cluster for Science RIKEN  Yokohama Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7112-2812","authenticated-orcid":false,"given":"Shinji","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics Janssen Research and Development, LLC  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Snoeys","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics Janssen Research and Development  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichi","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Sugiyama Laboratory, RIKEN Cluster for Science RIKEN  Yokohama Kanagawa Japan"},{"name":"Laboratory of Quantitative System Pharmacokinetics\/Pharmacodynamics Josai International University (JIU)  Tokyo 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