Drug Interaction Report

MONITOR: Coadministration with maribavir may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) efflux transporters, both of which have been shown to be inhibited in vitro by maribavir at clinically relevant concentrations. Inhibition of transporter-mediated efflux in the intestine and possibly other organs such as the liver and kidney can increase the systemic bioavailability and decrease the clearance of affected substrates. When a single 0.5 mg dose of digoxin, a sensitive P-gp substrate, was coadministered with maribavir 400 mg twice daily in 18 study subjects, mean digoxin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 25% and 21%, respectively, compared to digoxin administered alone. There are no clinical data regarding the use of maribavir with BCRP substrates, but increases in plasma concentrations of sensitive substrates such as rosuvastatin are expected according to the prescribing information.

MANAGEMENT: Caution is advised when maribavir is prescribed with drugs that are P-gp and/or BCRP substrates, particularly sensitive substrates or those with a narrow therapeutic range. Clinical and laboratory monitoring as well as dosage adjustments may be appropriate for some drugs whenever maribavir is added to or withdrawn from therapy.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 P-gp/BCRP inhibitors and for any dosage adjustments that may be required.

Coadministration with inhibitors of the isoenzyme CYP450 3A4 may increase the plasma concentrations and effects of maribavir, a CYP450 3A4 substrate. When a single 400 mg dose of maribavir was administered with a single 400 mg dose of ketoconazole, a potent CYP450 3A4 and P-glycoprotein (P-gp) inhibitor, mean maribavir peak plasma concentration (Cmax) and total systemic exposure (AUC) increased by 10% and 53%, respectively, in 19 study subjects. These changes are not considered clinically significant. No dosage adjustments are necessary when maribavir is prescribed with CYP450 3A4 inhibitors, but it may be advisable to monitor patients for maribavir-related adverse effects such as taste disturbances, nausea, diarrhea, vomiting, and fatigue.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.