{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T05:01:43Z","timestamp":1768971703294,"version":"3.49.0"},"reference-count":54,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T00:00:00Z","timestamp":1708905600000},"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":[[2024,6]]},"abstract":"<jats:p>Daprodustat is the first oral hypoxia\u2010inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B\u2010mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> studies, and physiologically\u2010based PK (PBPK) modeling of its drug\u2013drug interactions (DDIs) with inhibitor drugs. <jats:italic>In vitro<\/jats:italic>, daprodustat showed specific transport by OATP1B1\/1B3 in the transfected cell systems and primary human and monkey hepatocytes. A single\u2010dose oral rifampin (OATP1B inhibitor) reduced daprodustat intravenous clearance by a notable\u00a09.9\u2009\u00b1\u20091.2\u2010fold (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) in cynomolgus monkeys. Correspondingly, volume of distribution at steady\u2010state was also reduced by 5.0\u2009\u00b1\u20091.1\u2010fold, whereas the half\u2010life change was minimal (1.5\u2010fold), corroborating daprodustat hepatic uptake inhibition by rifampin. A PBPK model accounting for OATP1B\u2010CYP2C8 interplay was developed, which well described daprodustat PK and DDIs with gemfibrozil (CYP2C8 and OATP1B inhibitor) and trimethoprim (weak CYP2C8 inhibitor) within 25% error of the observed data in healthy subjects. About 18\u2010fold increase in daprodustat area under the curve (AUC) following gemfibrozil treatment was found to be associated with strong CYP2C8 inhibition and moderate OATP1B inhibition. Moreover, PK modulation in hepatic dysfunction and subjects with CKD, in comparison to healthy control, was well\u2010captured by the model. CYP2C8 and\/or OATP1B inhibitor drugs (e.g., gemfibrozil, clopidogrel, rifampin, and cyclosporine) were predicted to perpetrate moderate\u2010to\u2010strong DDIs in healthy subjects, as well as, in target CKD population. Daprodustat can be used as a sensitive CYP2C8 index substrate in the absence of OATP1B modulation.<\/jats:p>","DOI":"10.1002\/cpt.3215","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T08:58:59Z","timestamp":1708937939000},"page":"1336-1345","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Mechanistic Determinants of Daprodustat Drug\u2013Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of <scp>OATP1B\u2010CYP2C8<\/scp> Interplay"],"prefix":"10.1002","volume":"115","author":[{"given":"Yi\u2010An","family":"Bi","sequence":"first","affiliation":[{"name":"Pharmacokinetics, Dynamics, and Metabolism, Pfizer R&amp;D, Pfizer Inc.  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