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Altered Irinotecan Pharmacokinetics in Pediatric High-Grade Glioma Patients Receiving Enzyme-inducing Anticonvulsant Therapy¹

Departments of Pharmaceutical Sciences [K. R. C., C. F. S.], Biostatistics and Epidemiology [D. J-W.], Hematology-Oncology [S. J. T., R. L. H., M. F., A. G.], and Molecular Pharmacology [P. J. H.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; Division of Pediatric Hematology/Oncology, University of Texas Southwestern Medical School, Dallas, Texas 75235 [D. C. B.]; and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030 [M. M. C.]

Purpose: The purpose of this study was to determine the effect of enzyme-inducing anticonvulsants (EIAs) on the disposition of irinotecan and metabolites in pediatric patients with high-grade glioma.

Experimental Design: Pediatric patients with newly diagnosed high-grade glioma were enrolled on this study between March 1999 and February 2001. During course 1, irinotecan was administered as a 60-min i.v. infusion at a dosage of 20 mg/m²/day for 5 days of 2 consecutive weeks. On days 1 and 12 of course 1, we collected serial plasma samples to measure the concentrations of the lactone and total forms of irinotecan and its metabolites SN-38 (7-ethyl-10-hydroxycamptothecin), SN-38 glucuronide (7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]camptothecin), and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin.

Results: Thirty-one patients were enrolled. In patients receiving EIAs, the area under the concentration versus time curve (AUC) of irinotecan lactone and SN-38 lactone was significantly lower (P = 0.01 and P = 0.002, respectively), and the irinotecan lactone clearance was significantly higher (P = 0.0003), as compared with those in patients who received no EIAs. The glucuronidation ratio was higher (P = 0.0009), and the ratio of SN-38 AUC to irinotecan AUC was lower (P = 0.02) in patients who received EIAs. Two patients receiving EIAs tolerated increased irinotecan dosages of 30 and 40 mg/m²/day without toxicity. One patient receiving EIAs experienced grade 3 diarrhea when the dosage of irinotecan was increased to 60 mg/m²/day.

Conclusions: EIAs increase the clearance of irinotecan and cause a decrease in systemic exposure to the active metabolite SN-38. Patients who are receiving irinotecan and who require anticonvulsants should be placed on non-EIA therapy, when possible.

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