Drug Interaction Report

Coadministration with saquinavir/ritonavir may decrease the plasma concentrations of etravirine. The mechanism of interaction has not been described but may involve ritonavir induction of CYP450 2C19 and 2C9, of which etravirine is a substrate. In 14 study subjects administered etravirine with saquinavir/ritonavir (1000 mg/100 mg) twice a day, etravirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) decreased by 37%, 33% and 29%, respectively. These changes are similar to those observed when etravirine is coadministered with darunavir/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 saquinavir/ritonavir may be coadministered without any dosage adjustments.

ADJUST DOSING INTERVAL: Food significantly increases the absorption of saquinavir.

MONITOR: Coadministration with grapefruit juice may increase the plasma concentrations of saquinavir. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In eight healthy volunteers, ingestion of 400 mL of grapefruit juice prior to administration of a 600 mg dose of saquinavir mesylate increased the area under the plasma concentration-time curve and oral bioavailability of saquinavir by 50% and 100%, respectively, compared to water; however, the increase is not considered clinically relevant. A high degree of intersubject variability in the grapefruit juice effect was also observed. The extent to which this interaction may occur with the saquinavir free base soft gelatin capsule is unknown. However, the saquinavir soft gelatin capsule formulation is no longer commercially available.

MANAGEMENT: Saquinavir mesylate should be taken with meals or within 2 hours after eating to enhance bioavailability. Patients should be advised to avoid the consumption of large amounts of grapefruit and grapefruit juice during saquinavir therapy unless otherwise directed by their doctor, as the interaction is unreliable and subject to a high degree of interpatient variation.

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.