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Effect of intrapatient dosage escalation of irinotecan on its pharmacokinetics in pediatric patients who have high‐grade gliomas and receive enzyme‐inducing anticonvulsant therapy
Author(s) -
Gajjar Amar,
Chintagumpala Murali M.,
Bowers Daniel C.,
JonesWallace Dana,
Stewart Clinton F.,
Crews Kristine R.
Publication year - 2003
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.11308
Subject(s) - medicine , irinotecan , pharmacokinetics , anticonvulsant , oncology , pharmacology , cancer , epilepsy , colorectal cancer , psychiatry
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. Cancer 2003;97(9 Suppl):2374–80. © 2003 American Cancer Society. DOI 10.1002/cncr.10308