The effect of enzyme-inducing antiseizure drugs on the pharmacokinetics and tolerability of procarbazine hydrochloride

Stuart A. Grossman, Kathryn A. Carson, Tracy T. Batchelor, Glenn Lesser, Tom Mikkelsen, Jane B. Alavi, Surasak Phuphanich, Tarek Hammour, Joy D. Fisher, Jeffrey G. Supko

Research output: Contribution to journalArticle

Abstract

Purpose: Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum tolerated dose and pharmacokinetics of PCB are affected by the concurrent use of enzyme-inducing antiseizure drugs (EIASD). Experimental Design: Adults with recurrent high-grade glioma were divided into cohorts who were (+) and were not (-) taking EIASDs. PCB was given orally for 5 consecutive days each month. Six patients were evaluated at each dose level beginning with 200 mg/m2/d and escalated using the modified continual reassessment method. Toxicity and response were assessed. Pharmacokinetic studies were done with a new electrospray ionization mass spectrometry assay. Results: Forty-nine patients were evaluated. The maximum tolerated dose was 393 mg/m2/d for the +EIASD group and the highest dose evaluated in -EIASD patients was 334 mg/m2/d. Myelosuppression was the primary dose-limiting toxicity. Significant hepatic dysfunction occurred in three patients in the +EIASD cohort. Four partial responses (8%) and no complete responses were observed. PCB exhibited linear pharmacokinetics with no significant differences between the two cohorts. A marked increase in peak PCB levels was noted on day 5 relative to day 1, which was not attributable to drug accumulation. Conclusions: This study suggests that (a) EIASD use does not significantly affect the pharmacokinetics of PCB; (b) changes in the peak plasma concentration of PCB, consistent with decreased apparent oral clearance due to autoinhibition of hepatic metabolism, occur with daily dosing; and (c) severe hepatic dysfunction may accompany this administration schedule.

Original languageEnglish (US)
Pages (from-to)5174-5181
Number of pages8
JournalClinical Cancer Research
Volume12
Issue number17
DOIs
StatePublished - Sep 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Grossman, S. A., Carson, K. A., Batchelor, T. T., Lesser, G., Mikkelsen, T., Alavi, J. B., Phuphanich, S., Hammour, T., Fisher, J. D., & Supko, J. G. (2006). The effect of enzyme-inducing antiseizure drugs on the pharmacokinetics and tolerability of procarbazine hydrochloride. Clinical Cancer Research, 12(17), 5174-5181. https://doi.org/10.1158/1078-0432.CCR-06-0932