Effect of intrapatient dosage escalation of irinotecan on its pharmacokinetics in pediatric patients who have high-grade gliomas and receive enzyme-inducing anticonvulsant therapy

Amar Gajjar, Murali M. Chintagumpala, Daniel C. Bowers, Dana Jones-Wallace, Clinton F. Stewart, Kristine R. Crews

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The authors set out to determine the effect of intrapatient dose escalation of irinotecan on its disposition in pediatric patients with high-grade glioma who received concomitant enzyme-inducing anticonvulsants (EIAs). During Course 1, a 60-minute intravenous infusion of irinotecan (20 mg/m2 per day) was administered once daily for 5 days on each of 2 consecutive weeks. The authors measured the concentrations of the lactone forms of irinotecan and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide, and 7-ethyl-10-[4-N-(5- aminopeptanoic acid)-1-piperidinol-carbonyloxycamptothecin (APC) in serial plasma samples collected on Days 1 and 12 of Course 1. For the 6 patients who received EIAs but whose SN-38 areas under the concentration-time curve (AUCs) on Day 1 were below clinically significant levels, irinotecan dosage was increased, and subsequent pharmacokinetic studies were performed. Thirty-five patients were enrolled. The rate of irinotecan clearance was greater for patients who received EIAs than for those who did not (P = 0.0008), whereas systemic exposure to irinotecan (P = 0.02) and SN-38 (P = 0.0001) was lower for those treated with EIAs than for those who were not. Of the 6 patients whose irinotecan dosages were increased, 3 experienced an increase in the SN-38 AUC between Days 1 and 12. For 1 patient, the SN-38 AUC on Day 12 was lower than on Day 1; this result likely was due to an increased dose of EIAs during the same period. Despite irinotecan dose escalation to 60 and 80 mg/m2, the SN-38 AUCs for 2 patients did not increase to clinically significant levels. The type and grade of toxicity did not differ between the two patient groups. Increasing the dosage of irinotecan increased the SN-38 AUC in some patients who received concomitant EIA therapy.

Original languageEnglish (US)
Pages (from-to)2374-2380
Number of pages7
JournalCancer
Volume97
Issue number9 SUPPL.
StatePublished - May 1 2003

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irinotecan
Glioma
Anticonvulsants
Pharmacokinetics
Pediatrics
Enzymes
Therapeutics

Keywords

  • EIA
  • Intrapatient dosage escalation
  • Irinotecan
  • Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Effect of intrapatient dosage escalation of irinotecan on its pharmacokinetics in pediatric patients who have high-grade gliomas and receive enzyme-inducing anticonvulsant therapy. / Gajjar, Amar; Chintagumpala, Murali M.; Bowers, Daniel C.; Jones-Wallace, Dana; Stewart, Clinton F.; Crews, Kristine R.

In: Cancer, Vol. 97, No. 9 SUPPL., 01.05.2003, p. 2374-2380.

Research output: Contribution to journalArticle

Gajjar, Amar ; Chintagumpala, Murali M. ; Bowers, Daniel C. ; Jones-Wallace, Dana ; Stewart, Clinton F. ; Crews, Kristine R. / Effect of intrapatient dosage escalation of irinotecan on its pharmacokinetics in pediatric patients who have high-grade gliomas and receive enzyme-inducing anticonvulsant therapy. In: Cancer. 2003 ; Vol. 97, No. 9 SUPPL. pp. 2374-2380.
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abstract = "The authors set out to determine the effect of intrapatient dose escalation of irinotecan on its disposition in pediatric patients with high-grade glioma who received concomitant enzyme-inducing anticonvulsants (EIAs). During Course 1, a 60-minute intravenous infusion of irinotecan (20 mg/m2 per day) was administered once daily for 5 days on each of 2 consecutive weeks. The authors measured the concentrations of the lactone forms of irinotecan and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide, and 7-ethyl-10-[4-N-(5- aminopeptanoic acid)-1-piperidinol-carbonyloxycamptothecin (APC) in serial plasma samples collected on Days 1 and 12 of Course 1. For the 6 patients who received EIAs but whose SN-38 areas under the concentration-time curve (AUCs) on Day 1 were below clinically significant levels, irinotecan dosage was increased, and subsequent pharmacokinetic studies were performed. Thirty-five patients were enrolled. The rate of irinotecan clearance was greater for patients who received EIAs than for those who did not (P = 0.0008), whereas systemic exposure to irinotecan (P = 0.02) and SN-38 (P = 0.0001) was lower for those treated with EIAs than for those who were not. Of the 6 patients whose irinotecan dosages were increased, 3 experienced an increase in the SN-38 AUC between Days 1 and 12. For 1 patient, the SN-38 AUC on Day 12 was lower than on Day 1; this result likely was due to an increased dose of EIAs during the same period. Despite irinotecan dose escalation to 60 and 80 mg/m2, the SN-38 AUCs for 2 patients did not increase to clinically significant levels. The type and grade of toxicity did not differ between the two patient groups. Increasing the dosage of irinotecan increased the SN-38 AUC in some patients who received concomitant EIA therapy.",
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AU - Stewart, Clinton F.

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