Drug Interaction Report

GENERALLY AVOID: Coadministration with etravirine may decrease the plasma concentrations of clarithromycin and increase concentrations of the active metabolite, 14-hydroxy-clarithromycin. The mechanism is etravirine induction of CYP450 3A4, the isoenzyme that metabolizes clarithromycin to 14-hydroxy-clarithromycin. In 15 study subjects administered clarithromycin 500 mg twice a day with etravirine, clarithromycin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) decreased by 34%, 39% and 53%, respectively, while Cmax, AUC and Cmin of 14-hydroxy-clarithromycin increased by 33%, 21% and 5%, respectively. Etravirine Cmax, AUC, and Cmin also increased by over 40% each due to inhibition of its CYP450 3A4 metabolism by clarithromycin.

MANAGEMENT: Because 14-hydroxy-clarithromycin has demonstrated reduced activity relative to the parent drug against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered during coadministration of clarithromycin with etravirine. Therefore, alternatives to clarithromycin (e.g., azithromycin) should be considered for the treatment of MAC in patients receiving etravirine.

ADJUST DOSING INTERVAL: Coadministration with food increases the oral bioavailability of etravirine. The mechanism is unknown. Compared to administration following a meal, the systemic exposure (AUC) to etravirine was decreased by about 50% when the drug was administered under fasting conditions. The types of meal studied (ranging from 345 kilocalories containing 17 grams fat to 1160 kilocalories containing 70 grams fat) did not appear to make a difference with respect to impact on etravirine bioavailability.

MANAGEMENT: Etravirine should always be administered following a meal.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.