Drug Interaction Report

ADJUST DOSE: Coadministration with delavirdine may significantly increase the plasma concentrations of saquinavir. The mechanism is delavirdine inhibition of saquinavir metabolism via CYP450 3A4. According to the delavirdine labeling, coadministration of delavirdine (400 mg three times a day) and saquinavir (soft gel capsule, or SGC, 1000 mg three times a day) for 28 days increased the mean peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of saquinavir by 98%, 121% and 199%, respectively, compared to administration of saquinavir SGC 1200 mg three times a day without delavirdine. Saquinavir had no apparent effect on the pharmacokinetics of delavirdine based on comparison with historical data. When administered with saquinavir mesylate (i.e., hard gelatin capsule, or HGC), delavirdine has been reported to increase saquinavir plasma levels 5-fold.

MANAGEMENT: Given the magnitude of interaction, a reduction of saquinavir SGC dosage should be considered during coadministration with delavirdine. Product labeling for the individual agents states that appropriate dosages for this combination with respect to safety and efficacy have not been established, although some HIV experts recommend that saquinavir SGC be given at 800 mg three times a day with the standard dosage of delavirdine. No dosage recommendations are available for saquinavir HGC or for saquinavir (either SGC or HGC) in combination with ritonavir. Patients receiving saquinavir with delavirdine should be monitored for toxicity such as elevations in liver function tests and undue gastrointestinal disturbances.

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.