Effects of CYP2C19 inhibitors on mavacamten pharmacokinetics in rats based on UPLC-MS/MS

Abstract

ContextCYP2C19 is an important member of the human cytochrome P450 2C (CYP2C) family. Mavacamten is a novel treatment of patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) which was metabolized mainly by CYP2C19. ObjectiveIn this study, we firstly reported and validated a quantitative analysis method of mavacamten in rat plasma based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), which was applied to the drug-drug interaction (DDI) study between mavacamten and CYP2C19 inhibitors (fluvoxamine, fluoxetine and fluconazole) in rats. Materials and methodsVericiguat was used as the internal standard (IS), and the analyte and IS were measured with electrospray ion (ESI) source in positive ion mode on a XEVO TQ-S triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode. ResultsIn the scope of 1.0–100 ng/mL, this assay had excellent linearity. Both intra-day and inter-day accuracy of the analyte ranged from −2.4% to 9.1%, while the precision was ≤4.2%. Matrix effect, recovery, and stability were evaluated and validated to meet the requirements for the guidelines of bioanalytical assay. When compared with the control group, AUC0→∞ of mavacamten in fluconazole, fluoxetine and fluvoxamine were increased by 125.5%, 110.7% and 43.6%, respectively, which demonstrated that CYP2C19 inhibitors could inhibit mavacamten metabolism. ConclusionsThe results showed that CYP2C19 inhibitors could significantly improve the bioavailability of mavacamten in rats, which indicated that we should pay more attention to the patient's condition to prevent the occurrence of side effects when used mavacamten in combination with CYP2C19 inhibitors.