Drug Interaction Report

Coadministration with moderate or potent inhibitors of CYP450 3A4 and/or P-glycoprotein (P-gp) may increase the plasma concentrations (AUC) of vibegron, which has been shown in vitro to be a substrate of the isoenzyme and transporter. Although CYP450 3A4 is the predominant enzyme in vibegron metabolism, metabolic pathways have only a minor role in the elimination of vibegron. In a phase 3 Japanese study, coadministration of vibegron (100 mg) with moderate (diltiazem) and potent (ketoconazole) inhibitors of CYP450 3A4, resulted in a 1.6- and 2.1-fold increase in vibegron AUC, respectively, which was not considered clinically significant. No dosage adjustment is recommended when vibegron is administered in combination with moderate or potent CYP450 3A4 and/or P-gp inhibitors.

ADJUST DOSING INTERVAL: Food may reduce the oral bioavailability of lefamulin. When a single 600 mg oral dose of lefamulin was administered with a high-calorie, high-fat breakfast (800 to 1000 calories; approximately 50% from fat), lefamulin peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by approximately 23% and 18%, respectively.

GENERALLY AVOID: Grapefruit juice may increase the oral bioavailability of lefamulin. 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 pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, ketoconazole. When oral lefamulin was administered with oral ketoconazole, mean lefamulin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 58% and 165%, respectively. 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. Increased exposure to lefamulin may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Lefamulin tablets should be taken at least one hour before or two hours after a meal. Patients should preferably avoid or limit the consumption of grapefruit and grapefruit juice during treatment with lefamulin.