{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:22:12Z","timestamp":1770744132838,"version":"3.49.0"},"reference-count":18,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>Vicasinabin is an oral cannabinoid receptor 2 (CB2) agonist showing anti\u2010inflammatory effects and was developed for the treatment of chronic inflammatory diseases such as diabetic retinopathy. Vicasinabin is mainly metabolized by CYP3A4, with minor contributions from CYP2C19 and UGTs. The drug shows in\u00a0vitro induction of CYP3A4, as well as inhibition of hepatic and renal transporters. Translation of in\u00a0vitro data to a clinical drug\u2013drug interaction (DDI) risk assessment has been challenging, with a potential role of CYP2C19 genotypes in the pharmacokinetics to be considered. A physiologically based pharmacokinetic (PBPK) model of vicasinabin based on a bottom\u2010up approach predicted a moderate systemic exposure reduction for the selective CYP3A4 substrate midazolam. Neither the OATP1B1\/P\u2010gp\/CYP3A4 inhibition effect on atorvastatin nor the OCT2\/MATE1 inhibition effect on metformin was predicted to be of clinical relevance by PBPK modeling, as was confirmed by clinical DDI study data. After successful PBPK model prediction of itraconazole DDI using an in\u00a0vitro fm,CYP3A4 of 0.6, the model was applied to simulate weak or moderate exposure changes of vicasinabin after co\u2010administration with perpetrators for CYP3A4 and CYP2C19 (erythromycin, fluconazole, fluvoxamine, efavirenz, and rifampicin). A strong effect of induction due to rifampicin was also indicated. The CYP2C19 genotypes did not result in a significant impact on the victim DDI prediction for vicasinabin due to a low fm,CYP2C19 (\u223c0.2). The case study illustrated the usefulness of prospective PBPK predictions of clinical drug\u2013drug interactions using in\u00a0vitro data.<\/jats:p>","DOI":"10.1002\/cpt.3686","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T12:54:25Z","timestamp":1745844865000},"page":"428-437","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Prospective DDI Risk Assessment of Vicasinabin with PBPK Modeling by Integrating In\u00a0Vitro Data"],"prefix":"10.1002","volume":"118","author":[{"given":"Kenichi","family":"Umehara","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Roche Pharma Research and Early Development, Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6821-7714","authenticated-orcid":false,"given":"Neil","family":"Parrott","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Roche Pharma Research and Early Development, Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"G\u00fcnther","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Roche Pharma Research and Early Development, Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrijn","family":"Bogman","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Roche Pharma Research and Early Development, Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1097\/ICU.0000000000000362"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.survophthal.2015.06.001"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13226"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.841766"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.539"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2018.10.033"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12203"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.132"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.061523"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/tpj.2012.10"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1693"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2912"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-021-01346-2"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-022-01403-4"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1547"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1029073"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-023-01478-7"},{"key":"e_1_2_10_18_1","first-page":"191","article-title":"Estimation of fractions metabolized by hepatic CYP enzymes using a concept of inter\u2010system extrapolation factors (ISEFs) \u2013 a comparison with the chemical inhibition method","volume":"32","author":"Umehara K.","year":"2017","journal-title":"Drug Metab. 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Ther."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3686","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T08:52:02Z","timestamp":1752828722000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,28]]},"references-count":18,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/cpt.3686"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3686","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,28]]},"assertion":[{"value":"2024-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}