TY - JOUR T1 - Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.090092 SP - dmd.119.090092 AU - P. Kellie Turner AU - Stephen D Hall AU - Sonya C Chapman AU - Jessica Rehmel AU - Jane Royalty AU - Yingying Guo AU - Palaniappan Kulanthaivel Y1 - 2020/01/01 UR - http://dmd.aspetjournals.org/content/early/2020/06/24/dmd.119.090092.abstract N2 - Abemaciclib is an orally administered, potent inhibitor of cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and is metabolized extensively by cytochrome P450 (CYP) 3A4. The effects of abemaciclib on several CYPs were qualified in vitro and subsequently evaluated in a clinical study. In vitro, human hepatocytes were treated with vehicle, abemaciclib, or abemaciclib metabolites (M2, or M20). mRNA levels for 8 CYPs were measured using RT-qPCR and, additionally,catalytic activities for 3 CYPs were determined. In the clinical study, adult cancer patients received a drug cocktail containing CYP substrates (midazolam [3A], warfarin [2C9], dextromethorphan [2D6], and caffeine [1A2]) either alone or in combination with abemaciclib. Plasma PK samples were analyzed for all substrates, caffeine metabolite paraxanthine, and abemaciclib; polymorphisms of CYP2C9, CYP2D6, CYP3A4, and CYP3A5 were evaluated. In vitro, downregulation of CYP mRNA, including 1A2, 2B6, 2C8, 2C9, 2D6, and 3A, by abemaciclib and/or M2 and M20 was observed at clinically relevant concentrations. In humans, abemaciclib did not affect the PK of CYP2D6 or CYP2C9 substrates, and minor statistically significant but clinically irrelevant changes were observed for midazolam (AUC0-inf [13% lower] and Cmax [15% lower]), and caffeine (AUC0-inf [56% higher]) and paraxanthine: caffeine (AUC0-24 ratio [was approximately 30% lower]). However, given the magnitude of the effect, these changes are not considered clinically relevant. In conclusion, the downregulation of CYP mRNA mediated by abemaciclib in vitro did not translate into clinically meaningful drug-drug interactions in cancer patients.SIGNIFICANCE STATEMENT Despite observations that abemaciclib alters the mRNA of various CYP isoforms in vitro, a clinical study using a drug cocktail approach found no clinically meaningful drug-drug interactions between abemaciclib and a range of CYP substrates (midazolam [CYP3A4], S warfarin [CYP2C9], dextromethorphan [CYP2D6], and caffeine [CYP1A2]). This lack of translation suggests greater understanding of mechanisms of CYP downregulation is needed to accurately predict clinical DDI risk from in vitro data. ER -