Drug Interactions between lopinavir / ritonavir 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.

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

ADJUST DOSING INTERVAL: Food significantly increases the bioavailability of lopinavir from the oral solution formulation of lopinavir-ritonavir. Relative to fasting, administration of lopinavir-ritonavir oral solution with a moderate-fat meal (500 to 682 Kcal; 23% to 25% calories from fat) increased lopinavir peak plasma concentration (Cmax) and systemic exposure (AUC) by 54% and 80%, respectively, whereas administration with a high-fat meal (872 Kcal; 56% from fat) increased lopinavir Cmax and AUC by 56% and 130%, respectively. No clinically significant changes in Cmax and AUC were observed following administration of lopinavir-ritonavir tablets under fed conditions versus fasted conditions. Relative to fasting, administration of a single 400 mg-100 mg dose (two 200 mg-50 mg tablets) with a moderate-fat meal (558 Kcal; 24.1% calories from fat) increased lopinavir Cmax and AUC by 17.6% and 26.9%, respectively, while administration with a high-fat meal (998 Kcal; 51.3% from fat) increased lopinavir AUC by 18.9% but not Cmax. Relative to fasting, ritonavir Cmax and AUC also increased by 4.9% and 14.9%, respectively, with the moderate-fat meal and 10.3% and 23.9%, respectively, with the high-fat meal.

MANAGEMENT: Lopinavir-ritonavir oral solution should be taken with meals to enhance bioavailability and minimize pharmacokinetic variability. Lopinavir-ritonavir tablets may be taken without regard to meals.