Drug Interaction Report

MONITOR: Coadministration with inducers of the CYP450 3A4 isoenzyme may decrease the plasma concentrations of irinotecan and its pharmacologically active metabolite, SN-38. Irinotecan is partially metabolized by CYP450 3A4, and induction of this process results in less of the drug available in the plasma for conversion to SN-38 via carboxylesterases. The interaction has been reported with St. John's wort and the enzyme-inducing anticonvulsants carbamazepine, phenobarbital, and phenytoin. An approximately 40% reduction in SN-38 systemic exposure (AUC) has been reported in the presence of St. John's wort and greater than 60% reductions have been reported in the presence of enzyme-inducing anticonvulsants. However, all of these agents are known to be potent inducers of CYP450 3A4 as well as other enzymatic pathways (e.g., UDP-glucuronosyl transferase, or UGT; carboxylesterases) and drug transporters (e.g., multispecific organic anion transporter, or MRP2; P-glycoprotein) that may be involved in the clearance of irinotecan and/or SN-38. The extent, if any, to which irinotecan may interact with less potent CYP450 3A4 inducers is unknown.

MANAGEMENT: The antitumour activity of irinotecan may be reduced in patients treated with CYP450 3A4 inducers. Pharmacologic response to irinotecan should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the irinotecan dosage adjusted as necessary.

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.