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The concomitant use of nirmatrelvir\/ritonavir markedly increases tacrolimus blood concentrations. Although temporary discontinuation or dose reduction of tacrolimus at the start of nirmatrelvir\/ritonavir therapy is recommended in the package insert of this drug, little information is available on tacrolimus dosage adjustment when restarting. In this study, tacrolimus blood concentrations before and after nirmatrelvir\/ritonavir co\u2010administration were collected from national university hospitals across Japan, and population pharmacokinetic analysis was performed to develop an optimal dosing strategy for tacrolimus. In total, 83 tacrolimus blood concentrations from 15 patients were used in the analysis. First, the individual pharmacokinetic parameters of tacrolimus before the intake of nirmatrelvir\/ritonavir were estimated by post hoc Bayesian analysis using previously reported population pharmacokinetic parameters based on a two\u2010compartment model. The change in the relative bioavailability and clearance of tacrolimus after nirmatrelvir\/ritonavir administration was estimated by population pharmacokinetic modeling. Consequently, tacrolimus clearance was considered almost completely inhibited, and relative bioavailability increased 7.99\u2010fold with the co\u2010administration of nirmatrelvir\/ritonavir. The optimal dosing strategy based on the simulation was to withhold tacrolimus during nirmatrelvir\/ritonavir therapy and to restart tacrolimus at 10% of the baseline dose on day 1, followed by 20% on day 3% and 50% on day 6, and increased to 100% on day 9 after discontinuation of nirmatrelvir\/ritonavir, respectively. The proposed strategy will contribute to a safe and effective tacrolimus therapy when used in combination with nirmatrelvir\/ritonavir.<\/jats:p>","DOI":"10.1002\/psp4.70341","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:21:20Z","timestamp":1788754880000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Model\u2010Based Tacrolimus Dosing Using the Population Pharmacokinetic Analysis Under the Nirmatrelvir\/Ritonavir Therapy"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7982-7881","authenticated-orcid":false,"given":"Kotaro","family":"Itohara","sequence":"first","affiliation":[{"name":"Department of Pharmacy Kobe University Hospital  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0803-8823","authenticated-orcid":false,"given":"Yoshiki","family":"Katada","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics Kyoto University Hospital  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Hatayama","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Hirosaki University Hospital  Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7927-9977","authenticated-orcid":false,"given":"Toshiaki","family":"Igarashi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Tohoku University Hospital  Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiro","family":"Ogura","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Yamagata University Hospital  Yamagata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Yamanashi Hospital  Chuo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3698-5916","authenticated-orcid":false,"given":"Shingo","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Division of Pharmacy Chiba University Hospital  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Homma","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Tsukuba Hospital  Tsukuba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8671-5856","authenticated-orcid":false,"given":"Takashi","family":"Niwa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Gifu University Hospital  Gifu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9696-3422","authenticated-orcid":false,"given":"Yoshiaki","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy Nagoya University Hospital  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanae","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Kyushu University Hospital  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2657-4454","authenticated-orcid":false,"given":"Hideyuki","family":"Terazono","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Kagoshima University Hospital  Kagoshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7904-7132","authenticated-orcid":false,"given":"Hideo","family":"Shiohira","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of the Ryukyus Hospital  Ginowan Japan"},{"name":"Laboratory of Clinical Pharmacy Showa Pharmaceutical University  Machida Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4559-9753","authenticated-orcid":false,"given":"Tomohiro","family":"Terada","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics Kyoto University Hospital  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9517-5628","authenticated-orcid":false,"given":"Ikuko","family":"Yano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Kobe University Hospital  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"National Institute of Diabetes and Digestive and Kidney Diseases \u201cLiverTox: Clinical and Research Information on Drug\u2010Induced Liver Injury. 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