Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy

Kristine R. Crews, Clinton F. Stewart, Dana Jones-Wallace, Stephen J. Thompson, Peter J. Houghton, Richard L. Heideman, Maryam Fouladi, Daniel C. Bowers, Murali M. Chintagumpala, Amar Gajjar

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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)-l-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.

Original languageEnglish (US)
Pages (from-to)2202-2209
Number of pages8
JournalClinical Cancer Research
Volume8
Issue number7
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy'. Together they form a unique fingerprint.

  • Cite this

    Crews, K. R., Stewart, C. F., Jones-Wallace, D., Thompson, S. J., Houghton, P. J., Heideman, R. L., Fouladi, M., Bowers, D. C., Chintagumpala, M. M., & Gajjar, A. (2002). Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy. Clinical Cancer Research, 8(7), 2202-2209.