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The objective of the present study was to elucidate the contribution of these molecules to the nonlinear pharmacokinetics of GZR using a physiologically based pharmacokinetic (PBPK) model. Utilizing plasma concentration\u2013time profiles of GZR derived from reported dose\u2010escalation (50\u2013800\u2009mg) clinical studies and cumulative excretion data, around 10 parameters, including Michaelis constants (K<jats:sub>m<\/jats:sub>) for OATP1B, CYP3A, and P\u2010gp, were estimated via a cluster Gauss\u2013Newton method (CGNM). Parameter combinations that could reproduce the clinical data of GZR were obtained; however, discrepancies were noted between the in\u00a0vivo estimated K<jats:sub>m<\/jats:sub> and the corresponding in\u00a0vitro K<jats:sub>m<\/jats:sub>. Next, by incorporating the in\u00a0vitro K<jats:sub>m<\/jats:sub> values into our PBPK\u2013CGNM analyses utilizing a penalized parameter method, newly obtained parameter combinations appropriately reflected both the in\u00a0vivo and in\u00a0vitro observations. Particularly regarding OATP1B, while saturation of uptake was not clearly observed in the in\u00a0vitro experiments without human serum albumin (HSA), K<jats:sub>m<\/jats:sub> values capable of explaining in\u00a0vivo saturation were obtained under physiological HSA concentrations. By estimating the extent of saturation for each molecule in the liver and intestine and conducting sensitivity analyses of the K<jats:sub>m<\/jats:sub> values, it was inferred that OATP1B3 contributed the most to the nonlinearity of plasma GZR concentrations, followed by P\u2010gp. In conclusion, the PBPK\u2013CGNM, supplemented by penalized in\u00a0vitro parameters, was shown to be effective for analyzing complex pharmacokinetics involving drug transporters and enzymes.<\/jats:p>","DOI":"10.1002\/psp4.13314","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T05:01:56Z","timestamp":1739250116000},"page":"770-780","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Elucidating Contributions of Drug Transporters\/Enzyme to Nonlinear Pharmacokinetics of Grazoprevir by <scp>PBPK<\/scp> Modeling With a Cluster Gauss\u2013Newton Method"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2773-9761","authenticated-orcid":false,"given":"Takashi","family":"Yoshikado","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Pharmacology Yokohama University of Pharmacy  Yokohama Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5881-2023","authenticated-orcid":false,"given":"Yasunori","family":"Aoki","sequence":"additional","affiliation":[{"name":"Laboratory of Quantitative System Pharmacokinetics\/Pharmacodynamics, School of Pharmacy Josai International University  Tokyo Japan"},{"name":"Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacology Yokohama University of Pharmacy  Yokohama Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeko","family":"Shida","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacology Yokohama University of Pharmacy  Yokohama Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Laboratory of Quantitative System Pharmacokinetics\/Pharmacodynamics, School of Pharmacy Josai International University  Tokyo Japan"},{"name":"iHuman Institute ShanghaiTech University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7600-7813","authenticated-orcid":false,"given":"Koji","family":"Chiba","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacology Yokohama University of Pharmacy  Yokohama Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.123.001344"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.391"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12275"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2017.04.063"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.117.078972"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.117.079210"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2017.05.001"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11081-020-09571-2"},{"issue":"1","key":"e_1_2_9_10_1","first-page":"54","article-title":"Cluster Gauss\u2010Newton Method for a Quick Approximation of Profile Likelihood: With Application to Physiologically\u2010Based Pharmacokinetic Models","volume":"13","author":"Aoki Y.","year":"2024","journal-title":"Clinical Pharmacology & Therapeutics"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13154"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.122.000968"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.120.000023"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12849"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00813-17"},{"key":"e_1_2_9_16_1","unstructured":"L.Caro M.Anderson L.Du et\u00a0al. \u201cPharmacokinetics and Pharmacokinetic\/Pharmacodynamic Relationship for MK\u20105172 a Novel Hepatitis C Virus (HCV) NS3\/4A Protease Inhibitor in Genotype 1 and Genotype 3 HCV\u2010Infected Patients \u201d62th Annual Meeting of the American Association for the Study of Liver Diseases November 6\u20139th 2011. 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