Exposure-Response Modeling and Simulation to Identify Optimal Mavacamten Posology When Coadministered with CYP3A4 and...

Mavacamten, a cardiac myosin inhibitor, is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4, and coadministration with strong CYP3A4 or CYP2C19 inhibitors was contraindicated in patients with obstructive hypertrophic cardiomyopathy (HCM) in the US Prescribing Information. This study assessed the safety and efficacy of modifying mavacamten posology to accommodate coadministration with strong CYP3A4 and strong/moderate CYP2C19 inhibitors. Simulations of 5000 virtual patients with obstructive HCM with an equal distribution of CYP2C19 metabolizer phenotypes were performed using population pharmacokinetic and exposure-response modeling approaches. A reference posology and variations thereof were simulated to evaluate long-term (chronic) and short-term (1-week) coadministration with CYP3A4 or CYP2C19 inhibitors. Proportions of patients with left ventricular ejection fraction (LVEF) <50% and Valsalva left ventricular outflow tract gradient (VLVOTg) <30 mm Hg were evaluated to assess safety and efficacy, respectively. Compared with the reference posology, a modified posology, which used a 2.5-mg starting dose with coadministration being stopped if LVEF was <50% at any time when receiving 2.5 mg, resulted in a similar peak proportion of CYP2C19 poor metabolizers and CYP2C19 ultrarapid metabolizers with LVEF <50% when initiating mavacamten with a CYP3A4 or CYP2C19 inhibitor, respectively. Achievement of optimal efficacy was delayed in some patients owing to dose reduction. Initiation of CYP3A4 or CYP2C19 inhibitor treatment in patients receiving stable mavacamten therapy was accommodated through mavacamten dose reduction by one level. Interruption of mavacamten during short-term administration of inhibitors transiently increased VLVOTg for the duration of interruption, with no effect on LVEF.