Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of doravirine, which is primarily metabolized by the isoenzyme. In 10 study subjects, administration of a single 100 mg dose of doravirine with the potent CYP450 3A4 inducer rifampin (600 mg once daily) decreased doravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (C24hr) by an average of 57%, 88% and 97%, respectively, compared to administration of doravirine alone. When doravirine was administered with rifabutin 300 mg once daily in 12 study subjects, doravirine Cmax did not change, but AUC and C24hr decreased by an average of 50% and 68%, respectively. When doravirine 100 mg once daily was initiated following cessation of treatment with efavirenz 600 mg once daily in 17 study subjects, doravirine Cmax, AUC and C24hr decreased by an average of 35%, 62% and 85%, respectively, on the first day and 14%, 32% and 50%, respectively, 14 days later. The extent to which other, less potent CYP450 3A4 inducers may affect doravirine is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of doravirine should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.