CYP450 activity, drug interactions, and genetic polymorphisms: clinical relevance for the new selective cardiac myosin inhibitors.

INTRODUCTION: Several sarcomeric gene abnormalities associated with left ventricular thickening, hypercontractility, and high left ventricular ejection fraction define hypertrophic cardiomyopathy (HCM). Standard treatment options such as beta-adrenergic blockers, calcium channel blockers, and/or disopyramide improve symptoms in many patients, but have limited ability to modify disease progression. Two new cardiac myosin inhibitors (CMIs), mavacamten and aficamten, reduce the intensity of myosin - actin cross-bridge formation and could treat causes of HCM.

AREAS COVERED: Drug clearance concepts, relevant information pertaining to cytochrome P450 (CYP450) isoenzymes involved in the disposition of mavacamten and aficamten, genetic polymorphisms associated with CYP450 isoenzymes, and relevance of multi-drug interactions leading to changes in the systemic exposure of CMIs.

EXPERT OPINION: Both mavacamten and aficamten exhibit complex disposition and are extensively metabolized by CYP450 isoenzymes including CYP2C9, CYP2C19, and CYP2D6, which exhibit genetic polymorphisms. CYP3A4 contributes less to the metabolism of mavacamten and aficamten. However, CYP3A4 can influence the disposition of these CMIs and other drugs, as CYP3A4 is subjected to induction and inhibition, and modulation by inflammatory factors. Therefore, multi-drug interactions due to changes in the metabolic clearances of CMIs are expected in HCM patients with other chronic conditions and polypharmacy.