Quantification of the impact of enzyme-inducing antiepileptic drugs on irinotecan pharmacokinetics and SN-38 exposure

The population pharmacokinetic model reported here was developed using data from 2 phase 2 trials of irinotecan for treatment of malignant glioma to quantify the impact of concomitant therapy with enzyme-inducing antiepileptic drugs (EIAEDs) on irinotecan pharmacokinetics. Patients received weekly irinotecan doses of 100 to 400 mg/m², and plasma samples were collected and analyzed for irinotecan and its APC, SN-38, and SN-38G metabolites. Nonlinear mixed-effects modeling was employed for population pharmacokinetic analysis. Concomitant therapy with phenytoin, phenobarbital, or carbamazepine increased the clearances of irinotecan, SN-38, and SN-38G but not APC. SN-38 clearance was 2-fold higher with concomitant EIAED use, resulting in 40% lower SN-38 exposure. Evaluation of additional covariates revealed no clinically relevant effects of sex or concomitant corticosteroid use. The population pharmacokinetic model suggests that a 1.7-fold increase in irinotecan dose may compensate for decreases in SN-38 exposure in the presence of concomitant EIAEDs. Although slightly more conservative, this dose adjustment is consistent with those recommended based on increases in the maximally tolerated dose for malignant glioma patients receiving EIAEDs and may be an appropriate starting point for further investigation when extrapolating to other cancer types or alternative regimens.