Influence of anticonvulsants on the metabolism and elimination of irinotecan. A North American Brain Tumor Consortium preliminary report

Abstract

The hepatic metabolism and biliary secretion of irinotecan (CPT-11, Camptosar) and metabolites is complex and involves cytochrome P450 isoenzymes, carboxylesterases, glucuronosyltransferase, and the ATP-dependent export pumps MRP-2 and MXR. Enzyme-inducing antiepileptic drugs (EIAEDs) such as phenytoin and carbamazepine are known to induce several of the metabolic pathways relevant to ininotecan 's elimination. The North American Brain Tumor Consortium phase I study is designed to determine the maximum tolerated dose and pharmacokinetics of irinotecan given every 3 weeks to patients who are receiving EIAEDs. The EIAEDs have altered both the pharmacokinetics and pharmacodynamics of irinotecan. Peak concentrations and the area under the plasma-time curves for both irinotecan and SN-38 were significantly decreased in patients receiving EIAEDs. The recommended phase II dose of irinotecan administered every 3 weeks is 750 mg/m2 for patients who have been receiving stable doses of EIAEDs.