French-Speaking Network of Pharmacogenetics (RNPGx) Recommendations for Clinical Use of Mavacamten

Abstract

Mavacamten, the first drug in the class of β-cardiac myosin modulator, is used for the treatment of patients with hypertrophic cardiomyopathy. This orally administered drug demonstrates wide interpatient variability in pharmacokinetics parameters, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 poor metabolizers have increased exposure and are at increased risk of reduced cardiac hypercontractility. To ensure the safety of all patients, European Medicines Agency recommends CYP2C19 preemptive genotyping, and consecutively, to adapt maintenance and initial mavacamten doses, and to manage drug-drug interactions, according to CYP2C19 phenotype. In this article, we summarize evidence from the literature supporting the association between CYP2C19 phenotype and pharmacological features of mavacamten and provide, beyond biologic guidelines, therapeutic recommendations for the use of mavacamten based on CYP2C19 and CYP3A4/CYP3A5 genotype.

Figure 1

Principles of mavacamten dose adjustment based on CYP2C19 metabolizer status and drug–drug interactions. CYP, cytochrome; LVEF, left ventricular ejection fraction; LVOTg, left ventricular outflow tract gradient.

Figure 2

Prevalence of CYP2C19 poor metabolizers across different populations. Allelic frequency from the CPIC data. Alleles > 1/1,000 in minor allele frequency excepted *2 and *3 are: African¹ (*35, *9, *10), East Asian² (*5).

Figure 3

French‐speaking network of pharmacogenetics (RNPGx) recommendations for clinical use of mavacamten. Green Star = Essential Test; Yellow star = advisable test; Red star = possibly helpful test. (Picard et al. ¹⁹ )