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Because apixaban and rivaroxaban are predominantly eliminated by cytochrome P450 (CYP) 3A and P\u2010glycoprotein (P\u2010gp), concomitant use of combined P\u2010gp and strong CYP3A4 inhibitors and inducers should be avoided. Physiologically\u2010based pharmacokinetic models for apixaban and rivaroxaban were developed to estimate the net effect of CYP3A induction, P\u2010gp inhibition, and P\u2010gp induction by rifampicin. The disposition of rivaroxaban is more complex compared with apixaban because both hepatic and renal P\u2010gp is considered to contribute to rivaroxaban elimination. Furthermore, organic anion transporter\u20103, a renal uptake transporter, may also contribute the elimination of rivaroxaban from systemic circulation. The models were verified with observed clinical drug\u2013drug interactions with CYP3A and P\u2010gp inhibitors. With the developed models, the predicted area under the concentration time curve and maximum concentration ratios were 0.43 and 0.48, respectively, for apixaban, and 0.50\u20130.52 and 0.72\u20130.73, respectively, for rivaroxaban when coadministered with 600\u00a0mg multiple doses of rifampicin and that were very close to observed data. The impact of each of the elimination pathways was assessed for rivaroxaban, and inhibition of CYP3A led to a larger impact over intestinal and hepatic P\u2010gp. Inhibition of renal organic anion transporter\u20103 or P\u2010gp led to an overall modest interaction. The developed apixaban and rivaroxaban models can be further applied to the investigation of interactions with other P\u2010gp and\/or CYP3A4 inhibitors and inducers.<\/jats:p>","DOI":"10.1002\/psp4.12562","type":"journal-article","created":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T10:47:26Z","timestamp":1602154046000},"page":"659-669","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Physiologically\u2010Based Pharmacokinetic Modeling for the Prediction of a Drug\u2013Drug Interaction of Combined Effects on P\u2010glycoprotein and Cytochrome P450 3A"],"prefix":"10.1002","volume":"9","author":[{"given":"Yukio","family":"Otsuka","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Exploratory Development Astellas Pharma Inc. Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary P.","family":"Choules","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Exploratory Development Astellas Pharma Global Development Inc. Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L.","family":"Bonate","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Exploratory Development Astellas Pharma Global Development Inc. Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanji","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Exploratory Development Astellas Pharma Inc. 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