Physiologically Based Pharmacokinetic Modeling and Simulation of Mavacamten Exposure with Drug-Drug Interactions from CYP Inducers and Inhibitors by CYP2C19 Phenotype

Abstract

Mavacamten is a first-in-class, oral, selective, allosteric, reversible cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association functional class II-III obstructive hypertrophic cardiomyopathy. Mavacamten is metabolized in the liver, predominantly via cytochrome P450 (CYP) enzymes CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). A physiologically-based pharmacokinetic (PBPK) model was developed using Simcyp version 19 (Certara, Princeton, NJ). Following model verification, the PBPK model was used to explore the effects of strong CYP3A4 and CYP2C19 inducers, and strong, moderate, and weak CYP2C19 and CYP3A4 inhibitors on mavacamten pharmacokinetics (PK) in a healthy population, with the effect of CYP2C19 phenotype predicted for poor, intermediate, normal, and ultrarapid metabolizers. The PBPK model met the acceptance criteria for all verification simulations (> 80% of model-predicted PK parameters within 2-fold of those observed clinically). A weak induction effect was predicted when mavacamten was administered with a strong CYP3A4 inducer in poor metabolizers. Moderate reductions in mavacamten exposure were predicted with a strong CYP2C19/CYP3A4 inducer in all CYP2C19 phenotypes. Except for the effect of strong CYP2C19 inhibitors on ultrarapid metabolizers, steady-state area under plasma concentration-time curve and maximum plasma concentration values were weakly affected (< 2-fold) or not affected (< 1.25-fold), regardless of CYP2C19 phenotype. In conclusion, a fit-for-purpose PBPK model was developed and verified, which accurately predicted the available clinical data and was used to simulate the potential impact of CYP induction and inhibition on mavacamten PKs, stratified by CYP2C19 phenotype.