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

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 17 Pg. 5174-81 (Sep 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16951236 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anticonvulsants
• Antineoplastic Agents
• Procarbazine

Topics

• Administration, Oral
• Adult
• Aged
• Anticonvulsants (administration & dosage, pharmacology)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Cohort Studies
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Enzyme Induction (drug effects)
• Female
• Follow-Up Studies
• Glioma (drug therapy, enzymology)
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Procarbazine (administration & dosage, adverse effects, pharmacokinetics)
• Spectrometry, Mass, Electrospray Ionization (methods)
• Time Factors
• Treatment Outcome