Model‐Informed Recommendation of Mavacamten Posology for Chinese Adults With Obstructive Hypertrophic Cardiomyopathy

ABSTRACT Mavacamten is a cardiac myosin inhibitor for adults with obstructive hypertrophic cardiomyopathy (HCM). Dose optimization is performed 4 weeks after starting mavacamten, guided by periodic echo measurements of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Previously, a population pharmacokinetic (PPK) model was developed and exposure‐response (E‐R) of VLVOTg (efficacy) and LVEF (safety) was used to identify the mavacamten titration regimen with the optimal benefit/risk ratio, now included in the US prescribing information. Mavacamten is metabolized primarily by cytochrome P450 2C19 (CYP2C19) (74%), a highly polymorphic enzyme. China has a higher prevalence of poor CYP2C19 metabolizer phenotype compared with the global population; therefore, a previous model was adapted to include Chinese patients with obstructive HCM to identify the optimal dosing regimen for this population. Data from a phase I (healthy Chinese volunteers) and a phase III (EXPLORER‐CN, NCT05174416; Chinese patients with obstructive HCM) trial of mavacamten were added to the previous PPK and E‐R models, and the observed VLVOTg and LVEF from EXPLORER‐CN were successfully simulated. Next, five echocardiography‐guided titration regimens (plus the EXPLORER‐CN regimen) using representative or equal CYP2C19 phenotypes were simulated. The final simulated regimen recommended with an optimal benefit/risk profile across CYP2C19 phenotypes included: down‐titration at Week 4 (if VLVOTg < 20 mmHg), restart at Week 12, and up‐titration at Week 12 (for VLVOTg ≥ 30 mmHg and LVEF ≥ 55%), and every 12 weeks thereafter. This supports the previously recommended regimen for Chinese patients with obstructive HCM, now approved by the National Medicinal Products Administration.