Drug Interactions between mavacamten and Prevpac

CONTRAINDICATED: Coadministration with moderate to potent inhibitors of CYP450 2C19 or potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of mavacamten. Because mavacamten reduces systolic contraction and left ventricular ejection fraction, increased exposure may potentiate the risk of heart failure. According to the prescribing information, mavacamten is primarily metabolized by CYP450 2C19 (74%) and to a lesser extent by CYP450 3A4 (18%) and 2C9 (8%). In healthy CYP450 2C19 normal and rapid metabolizers, concomitant use of mavacamten (15 mg) with the weak CYP450 2C19 inhibitor omeprazole (20 mg) once daily increased mavacamten systemic exposure (AUC) by 48% but had no effect on peak plasma concentration (Cmax). Potent inhibitors such as fluconazole, fluoxetine, fluvoxamine, or ticlopidine may be expected to increase mavacamten exposure to a significantly greater extent, although data are currently lacking. Concomitant use of mavacamten (15 mg) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily) is predicted to increase mavacamten AUC and Cmax by up to 130% and 90%, respectively.

MANAGEMENT: Concomitant use of mavacamten with moderate to potent CYP450 2C19 inhibitors or potent CYP450 3A4 inhibitors is considered contraindicated.

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

MONITOR: Coadministration with mavacamten may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4, 2C9, and/or 2C19. The proposed mechanism is accelerated clearance due to induction of these isoenzymes by mavacamten. The interaction may be particularly important for sensitive substrates or those that demonstrate a narrow therapeutic index. When midazolam, a probe substrate for CYP450 3A4, was coadministered with a 16-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 14 days) in healthy CYP450 2C19 normal metabolizers, midazolam peak plasma concentration (Cmax) decreased by 7% and systemic exposure (AUC) decreased by 13%. Following coadministration of mavacamten once daily in patients with obstructive hypertrophic cardiomyopathy (HCM), midazolam Cmax and AUC are predicted to decrease by 13% to 48% and 21% to 64%, respectively, depending on the dose of mavacamten and CYP450 2C19 phenotype. Additionally, concomitant use of mavacamten once daily in HCM patients is predicted to decrease the Cmax and AUC of repaglinide, a CYP450 2C8 and 3A4 substrate, by 12% to 39%; the Cmax and AUC of tolbutamide, a CYP450 2C9 substrate, by 33% to 65%; and the Cmax and AUC of omeprazole, a CYP450 2C19 substrate, by 48% to 67%, depending on the dose of mavacamten and CYP450 2C19 phenotype.

MANAGEMENT: Caution is advised when mavacamten is used concomitantly with drugs that are substrates of CYP450 3A4, 2C9 and/or 2C19, particularly sensitive substrates or those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever mavacamten is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a CYP450 inducer like mavacamten and for any dosage adjustments that may be required.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.