This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grossman, S. A. Articles by Supko, J. G. Search for Related Content PubMed PubMed Citation Articles by Grossman, S. A. Articles by Supko, J. G.

The Effect of Enzyme-Inducing Antiseizure Drugs on the Pharmacokinetics and Tolerability of Procarbazine Hydrochloride

Authors' Affiliations: ¹ The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland; ² Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; ³ Wake Forest University School of Medicine, Winston-Salem, North Carolina; ⁴ Henry Ford Health Science Center, Detroit, Michigan; ⁵ Hematology-Oncology Division, University of Pennsylvania, Philadelphia, Pennsylvania; and ⁶ Emory University School of Medicine, Atlanta, Georgia

Requests for reprints: Stuart A. Grossman, New Approaches to Brain Tumor Therapy Central Office, Johns Hopkins University, 1550 Orleans Street, CRB2-IM-16, Baltimore, MD 21231-1000. Phone: 410-955-3657; Fax: 410-614-9335; E-mail: grossman{at}jhmi.edu or jfisher{at}jhmi.edu.

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.

This article has been cited by other articles:

				K. A. Carson, S. A. Grossman, J. D. Fisher, and E. G. Shaw Prognostic Factors for Survival in Adult Patients With Recurrent Glioma Enrolled Onto the New Approaches to Brain Tumor Therapy CNS Consortium Phase I and II Clinical Trials J. Clin. Oncol., June 20, 2007; 25(18): 2601 - 2606. [Abstract] [Full Text] [PDF]

				L. L. Muldoon, C. Soussain, K. Jahnke, C. Johanson, T. Siegal, Q. R. Smith, W. A. Hall, K. Hynynen, P. D. Senter, D. M. Peereboom, et al. Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check J. Clin. Oncol., June 1, 2007; 25(16): 2295 - 2305. [Abstract] [Full Text] [PDF]