Hoch, Matthias, Sengupta, Tirtha and Hourcade-Potelleret, Florence (2022) Pharmacokinetic Drug Interactions of Asciminib With the Sensitive Cytochrome P450 Probe Substrates Midazolam, Warfarin and Repaglinide in Healthy Volunteers. Clinical and translational science. ISSN 1752-8062; 1752-8054

Abstract

Asciminib, a novel agent being investigated in chronic myeloid leukemia, is a first-in-class BCR-ABL1 inhibitor that works by STAMP (Specifically Targeting the ABL Myristoyl Pocket) and therefore differs from approved ATP-competitive tyrosine kinase inhibitors. In vitro, asciminib has shown reversible inhibition of cytochrome P450 (CYP) 3A4/5, CYP2C9 and CYP2C8. This phase 1, open-label, 2-stage study in healthy volunteers evaluated the effect of asciminib (40 mg twice daily at steady-state) as a potential perpetrator on single-dose pharmacokinetics of a 2-drug cocktail containing midazolam (CYP3A substrate) and warfarin (CYP2C9 substrate) in stage 1 (n=22), and of repaglinide (CYP2C8 substrate) in stage 2 (n=25). For midazolam plus asciminib vs midazolam, geometric mean (Gmean) ratios (90% confidence interval) for midazolam AUCinf and Cmax were 1.28 (1.15, 1.43) and 1.11 (0.96-1.28), respectively. For warfarin plus asciminib vs warfarin, Gmean ratios for S-warfarin AUCinf and Cmax were 1.41 (1.37, 1.45) and 1.08 (1.04, 1.13). Results for R-warfarin were in line with those for S-warfarin. For repaglinide plus asciminib vs repaglinide, Gmean ratios for AUCinf and Cmax were 1.08 (1.02, 1.14) and 1.14 (1.01-1.28), respectively. The treatments were generally well tolerated, and the asciminib safety profile was consistent with previous reports with asciminib monotherapy. Overall, the results indicate that asciminib (40 mg twice daily) is a weak inhibitor of CYP3A and CYP2C9 and has no effect on CYP2C8.

Item Type:	Article
Date Deposited:	11 Jun 2022 00:45
Last Modified:	11 Jun 2022 00:45
URI:	https://oak.novartis.com/id/eprint/45824