title: Effect of intrapatient dosage escalation of irinotecan on its pharmacokinetics in pediatric patients who have high-grade gliomas and receive enzyme-inducing anticonvulsant therapy.
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/m(2) 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-piperidino]-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/m(2), 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.
authors.affiliation: Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. amar.gajjar@stjude.org
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Murali M
authors.initials: MM
authors.lastname: Chintagumpala
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bowers
authors.forename: Dana
authors.initials: D
authors.lastname: Jones-Wallace
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Crews
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004359:Drug Therapy, Combination; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D012449:Safety
chemical_list: D000927:Anticonvulsants; D000972:Antineoplastic Agents, Phytogenic; C100720:RPR 121056; D000077146:Irinotecan; D002166:Camptothecin