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

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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
Externally publishedYes

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irinotecan
Glioma
Anticonvulsants
Pharmacokinetics
Pediatrics
Enzymes
Lactones
Therapeutics
Area Under Curve

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy. / Crews, Kristine R.; Stewart, Clinton F.; Jones-Wallace, Dana; Thompson, Stephen J.; Houghton, Peter J; Heideman, Richard L.; Fouladi, Maryam; Bowers, Daniel C.; Chintagumpala, Murali M.; Gajjar, Amar.

In: Clinical Cancer Research, Vol. 8, No. 7, 01.01.2002, p. 2202-2209.

Research output: Contribution to journalArticle

Crews, KR, Stewart, CF, Jones-Wallace, D, Thompson, SJ, Houghton, PJ, Heideman, RL, Fouladi, M, Bowers, DC, Chintagumpala, MM & Gajjar, A 2002, 'Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy', Clinical Cancer Research, vol. 8, no. 7, pp. 2202-2209.
Crews, Kristine R. ; Stewart, Clinton F. ; Jones-Wallace, Dana ; Thompson, Stephen J. ; Houghton, Peter J ; Heideman, Richard L. ; Fouladi, Maryam ; Bowers, Daniel C. ; Chintagumpala, Murali M. ; Gajjar, Amar. / Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy. In: Clinical Cancer Research. 2002 ; Vol. 8, No. 7. pp. 2202-2209.
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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.",
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T1 - Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy

AU - Crews, Kristine R.

AU - Stewart, Clinton F.

AU - Jones-Wallace, Dana

AU - Thompson, Stephen J.

AU - Houghton, Peter J

AU - Heideman, Richard L.

AU - Fouladi, Maryam

AU - Bowers, Daniel C.

AU - Chintagumpala, Murali M.

AU - Gajjar, Amar

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N2 - 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.

AB - 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.

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