Interactions between cytadren(aminoglutethimide) and Camptosar (irinotecan)
aminoglutethimide and irinotecan (Moderate Drug-Drug)
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. In one study, irinotecan pharmacokinetics were determined in a 15-year-old boy on day 1 of two treatment cycles (50 mg/m2 daily for 5 days every 21 days)--one before and one after the addition of phenytoin, a known inducer of CYP450 3A4. The area under the plasma concentration-time curve (AUC) of irinotecan and its active metabolite decreased by 63% and 60%, respectively, following addition of phenytoin therapy. Irinotecan clearance was increased by 168%. In a phase II clinical trial, patients receiving irinotecan for malignant glioma had an unusually low incidence of toxicity, and AUCs of irinotecan and SN-38 were 40% and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer. A pharmacokinetic interaction was suspected, as more than 90% of the glioma patients received concomitant enzyme-inducing anticonvulsants and/or dexamethasone, while the colorectal cancer patients did not.
MANAGEMENT: The antitumor 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 Pharmacologic response to irinotecan should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the irinotecan dosage adjusted as necessary.
