Drug Interaction Report

CONTRAINDICATED: Coadministration with atazanavir, atazanavir-ritonavir or atazanavir-cobicistat is predicted to significantly increase the plasma concentrations of irinotecan and its metabolite, SN-38. CYP450 3A4 and UGT1A1 are the isoenzymes 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 another potent CYP450 3A4 and UGT1A1 inhibitor, ketoconazole, resulted in a 100% increase in the relative exposure to SN-38 and an 87% reduction in the exposure to APC.

MANAGEMENT: Concomitant use of irinotecan with atazanavir, atazanavir-ritonavir or atazanavir-cobicistat is considered contraindicated by some authorities. Atazanavir-ritonavir should be discontinued for at least one week before initiation of treatment with irinotecan.

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.