Drug Interactions between doravirine / lamivudine / tenofovir disoproxil and rifabutin

GENERALLY AVOID: Coadministration with inducers of P-glycoprotein (P-gp) may decrease the oral bioavailability and plasma concentrations of tenofovir alafenamide (TAF), which is a substrate of the efflux transporter. In 26 healthy study subjects, administration of TAF (25 mg once daily) with the P-gp inducer carbamazepine (300 mg twice daily) decreased TAF plasma concentration (Cmax) and systemic exposure (AUC) by an average of 57% and 55%, respectively, compared to TAF administered alone. It is not known if, and to what extent, tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, may interact with P-gp inducers. The interaction has not been studied with TDF, and no information is found in the labeling of various products containing TDF, although it has been reported to be a P-gp substrate also.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of tenofovir alafenamide fumarate with P-gp inducers is not recommended. Whether this also applies to tenofovir disoproxil fumarate has not been established.

ADJUST DOSE: Coadministration with rifabutin may significantly decrease the plasma concentrations of doravirine. The mechanism is rifabutin induction of doravirine metabolism via CYP450 3A4. When a single 100 mg dose of doravirine was administered with rifabutin 300 mg once daily in 12 study subjects, doravirine peak plasma concentration (Cmax) did not change, but systemic exposure (AUC) and trough plasma concentration (C24hr) decreased by an average of 50% and 68%, respectively, compared to doravirine administered alone. Reduced efficacy of doravirine may occur.

MANAGEMENT: When used with rifabutin, doravirine dosage should be increased to 100 mg twice daily (approximately 12 hours apart) for the duration of rifabutin coadministration. Otherwise, doravirine should not be initiated until at least 4 weeks after cessation of rifabutin.