Pharmacokinetic drug interactions of asciminib with the sensitive cytochrome P450 probe substrates midazolam, warfarin, and repaglinide in healthy participants

• DOI: 10.1111/cts.13252
• Publication Date: 2022-03-16T06:40:55Z
• Authors: Matthias Hoch; Tirtha Sengupta; Florence Hourcade...
• Keywords: Repaglinide; CYP2C8; CYP3A; Midazolam

Abstract Asciminib, a first‐in‐class BCR‐ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP), is new treatment option for patients with chronic myeloid leukemia who no longer benefit from currently approved tyrosine kinase inhibitors. In vitro, asciminib reversibly inhibits cytochrome P450 (CYP) 3A4/5, CYP2C9, and CYP2C8. This phase I, open‐label, two‐stage study in healthy participants evaluated effect of (40 mg b.i.d. at steady‐state) as potential perpetrator on single‐dose pharmacokinetics two‐drug cocktail containing midazolam (CYP3A substrate) warfarin (CYP2C9 stage 1 ( n = 22), repaglinide (CYP2C8 2 25). For plus versus midazolam, geometric mean G ) ratios (90% confidence interval) area under curve zero to infinity (AUC inf maximum plasma concentration (C max were 1.28 (1.15, 1.43) 1.11 (0.96, 1.28), respectively. warfarin, S‐warfarin AUC C 1.41 (1.37, 1.45) 1.08 (1.04, 1.13), Results R‐warfarin line those S‐warfarin. repaglinide, (1.02, 1.14) 1.14 (1.01, The treatments generally well tolerated, safety profile was consistent previous studies absence probe substrates. Overall, results indicate b.i.d.) weak CYP3A CYP2C9 has meaningful