Abstract 12412: In Silico Evaluation of Dosing Regimens to Accommodate Coadministration of Mavacamten With Strong Inhibitors of Cytochrome P450 3A4 and Moderate Inhibitors of Cytochrome P450 2C19 in Patients With Obstructive Hypertrophic Cardiomyopathy

Abstract

Background: Mavacamten is primarily metabolized by cytochrome P450 enzymes CYP2C19 and CYP3A4 and coadministration with strong CYP3A4 or moderate CYP2C19 inhibitors is contraindicated in patients with obstructive hypertrophic cardiomyopathy (HCM) in the US prescribing information (USPI). Aim: To assess the safety and efficacy of accommodating coadministration of mavacamten with strong CYP3A4 and moderate CYP2C19 inhibitors via simulations. Methods: Simulations of 5000 virtual patients with obstructive HCM uniformly distributed by CYP2C19 metabolizer phenotypes were performed using population pharmacokinetic and pharmacodynamic models. The USPI posology and variations were simulated to evaluate if short term (1 week) and long term (chronic) coadministration of CYP3A4 or CYP2C19 inhibitors could be accommodated. Analogous to USPI posology development, comparisons were made by evaluating proportions of patients with left ventricular ejection fraction [LVEF] < 50% (safety) and Valsalva left ventricular outflow tract gradient [VLVOTg] < 30 mmHg (efficacy). Results: When initiating mavacamten with a CYP3A4 inhibitor, a posology using 2.5 mg starting dose, with coadministration stopped if LVEF < 50% at 2.5 mg, resulted in a similar peak proportion of CYP2C19 poor metabolizers with LVEF < 50% (5.7%) and LVEF < 40% (0.9%) compared to the USPI (2.7% and 0.3% respectively; Table ). When initiating mavacamten with a CYP2C19 inhibitor, a 2.5 mg starting dose resulted in a similar peak proportion of LVEF < 50% in CYP2C19 ultrarapid metabolizers to USPI. Optimal efficacy was achieved; in some patients, this was delayed owing to dose reduction. Interruption of mavacamten during short term administration of inhibitors transiently increased VLVOTg for the duration of interruption, with no effect on LVEF. Conclusion: Coadministration of mavacamten with CYP3A4 or CYP2C19 inhibitors could be accommodated within the titration scheme with dose interruption or down titration.