Drug Interactions between gepirone and mavacamten

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of mavacamten. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. 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%). When mavacamten (25 mg) was coadministered with the moderate CYP450 3A4 inhibitor verapamil (sustained-release 240 mg) in intermediate and normal metabolizers of CYP450 2C19, mavacamten systemic exposure (AUC) increased by 15% and peak plasma concentration (Cmax) increased by 52%. Concomitant use of mavacamten with diltiazem, another moderate CYP450 3A4 inhibitor, in CYP450 2C19 poor metabolizers is predicted to increase mavacamten AUC and Cmax by up to 55% and 42%, respectively. 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. Because mavacamten reduces systolic contraction and left ventricular ejection fraction, increased exposure may potentiate the risk of heart failure. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Food does not affect the extent of absorption of mavacamten. No clinically significant difference in mavacamten exposure was observed following administration with a high-fat meal. However, the time to reach peak plasma concentration (Tmax) was increased by 4 hours.

MANAGEMENT: Mavacamten may be administered with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with mavacamten.

GENERALLY AVOID: Grapefruit and/or grapefruit juice may increase the plasma concentrations and effects of gepirone. The proposed mechanism is inhibition of CYP450 3A4 mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. For example, when subjects who were at steady state on the strong CYP450 3A4 inhibitor ketoconazole (200 mg twice daily) received a single dose of gepirone (36.3 mg), the maximum plasma concentration (Cmax) and systemic exposure (AUC) of gepirone increased by approximately 5-fold. Similarly, when subjects who were at steady state on the moderate CYP450 3A4 inhibitor verapamil (80 mg three times daily) received a single dose of gepirone (18.2 mg), the maximum plasma concentration (Cmax) and systemic exposure (AUC) of gepirone increased by approximately 2.6-fold. In general, the effects of grapefruit products are concentration-, dose-, and preparation-dependent and can vary widely among both brands and individual patients. Some preparations have demonstrated strong CYP450 3A4 inhibition, while others have demonstrated moderate inhibition.

ADJUST DOSING INTERVAL: Food enhances the bioavailability of gepirone and its major active metabolites (3'-OH-gepirone and 1-PP). The magnitude of the effect is dependent on the fat content of the meal, but the systemic exposure of gepirone and its major metabolites was consistently higher under fed conditions as compared to the fasted state. The peak plasma concentration (Cmax) of gepirone after intake of a low-fat (about 200 calorie) breakfast was 27% higher, after a medium-fat (about 500 calorie) breakfast was 55% higher, and after a high-fat (about 850 calorie) breakfast was 62% higher than the Cmax achieved in the fasted state. Likewise, the systemic exposure (AUC) of gepirone was about 14% higher after a low-fat breakfast, 22% higher after a medium-fat breakfast, and 32% to 37% higher after a high-fat breakfast when compared to the AUC achieved in the fasted state. The effect of varying amounts of fat on the AUC and Cmax of 3'-OH-gepirone and 1-PP were similar to that of gepirone.

MANAGEMENT: Coadministration of gepirone with grapefruit products should be avoided. If grapefruit juice is consumed, monitoring for adverse effects (e.g., QT prolongation, serotonin syndrome, dizziness, nausea, insomnia, abdominal pain, and/or dyspepsia) should be considered. Gepirone should be taken orally with food at the approximately the same time each day. Tablets should be swallowed whole.