Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of irinotecan and its active metabolite, SN-38. CYP450 3A4 is the isoenzyme responsible for the metabolic conversion of irinotecan to its inactive metabolite, APC. Inhibition of APC formation results in more irinotecan metabolism to SN-38, an active and toxic metabolite. High plasma levels of irinotecan and SN-38 may increase the risk of potentially fatal toxicities such as severe diarrhea, neutropenia, sepsis, and thromboembolism. In cancer patients, coadministration of ketoconazole, a potent CYP450 3A4 inhibitor, resulted in a 100% increase in the relative exposure to SN-38 and an 87% reduction in the exposure to APC. In HIV patients with Kaposi's sarcoma, coadministration of irinotecan with lopinavir-ritonavir decreased the clearance of irinotecan by 47%, increased the AUC of SN-38 by 204%, and decreased the AUC of APC by 81%.

MANAGEMENT: Concomitant use of irinotecan with potent CYP450 3A4 inhibitors should generally be avoided. Potent CYP450 3A4 inhibitors should be discontinued for at least one week before initiation of treatment with irinotecan.

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.