Drug Interactions between amoxicillin / omeprazole / rifabutin and etravirine

GENERALLY AVOID: (Only if etravirine is also coadministered with darunavir/ritonavir or saquinavir/ritonavir) Coadministration with rifabutin may decrease the plasma concentrations of etravirine. The mechanism is rifabutin induction of etravirine metabolism via CYP450 3A4. In 12 study subjects administered etravirine with rifabutin 300 mg once a day, etravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) decreased by approximately one-third each. These decreases are similar to those observed when etravirine is coadministered with darunavir/ritonavir or saquinavir/ritonavir. Because all subjects in Phase 3 trials of etravirine received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, etravirine and rifabutin may be coadministered without any dosage adjustments. However, in the presence of darunavir/ritonavir or saquinavir/ritonavir, further reductions in the plasma concentrations of etravirine may occur.

Etravirine may also decrease the plasma concentrations of rifabutin and its active metabolite, 25-O-desacetylrifabutin. In the study, Cmax, AUC and Cmin of rifabutin decreased by 10%, 17% and 24%, respectively, while those of 25-O-desacetylrifabutin decreased by 15%, 17% and 22%, respectively. The clinical significance of these changes are unknown.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, rifabutin should not be prescribed if etravirine is coadministered with darunavir/ritonavir or saquinavir/ritonavir. Rifabutin 300 mg once a day is recommended if etravirine is not coadministered with a protease inhibitor/ritonavir combination.

MONITOR: Coadministration of etravirine with a drug that is both a substrate as well as inhibitor of CYP450 2C19 and/or 2C9 may result in increased plasma concentrations of both drugs. Etravirine itself is also a substrate and inhibitor of CYP450 2C19 and 2C9. Theoretically, metabolism of etravirine and the coadministered drug may be mutually inhibited when used in combination. In 18 study subjects administered etravirine with the CYP450 2C19 inhibitor omeprazole (40 mg once a day), etravirine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 17% and 41%, respectively. The effect of etravirine on omeprazole pharmacokinetics was not reported.

MANAGEMENT: Because safety data regarding increased etravirine exposures are limited, caution is advised if etravirine is prescribed in combination with a CYP450 2C19 or 2C9 inhibitor. In addition, dosage adjustments may be required for the coadministered drug if it is also a substrate of CYP450 2C19 or 2C9.