Treatment > Procarbazine

Meeting Abstract

Pharmacokinetics of procarbazine and metabolites involved in its bioactivation in patients with recurrent anaplastic astrocytoma

Jeffrey G Supko, Xiaoying He, Carolyn Whitney, Tracy Batchelor, Thomas Mikkelsen, Jane Alavi, Surasak Phuphanich, Stuart Grossman

New Approaches To Brain Tumor Therapy Consortium, Baltimore, MD

Purpose. To characterize the pharmacokinetics (PK) and metabolism of procarbazine (PCZ) during a phase I trial in brain cancer patients stratified by concurrent use of enzyme inducing anticonvulsants (EIAs).

Methods. PCZ was given orally once a day for 5 days every 4 weeks.
The dose was escalated from 200 mg/m²/day in cohorts of 6 patients per dose level.
Sampling was performed to define complete plasma profiles on day 1 and peak concentrations (C_max) on day 5.

Results. LC/MS assays for PCZ and its azo-, methylazoxy-, and benzylazoxy- metabolites have been developed and validated.
The limit of quantitation for each analyte was 0.5-1.0 ng/ml in plasma.
There were no significant differences in mean PK parameters for the first daily dose of 294 mg/m² PCZ between the two groups.
Drug absorption was rapid with C_max occurring 0.6-1.0 h after dosing.
PCZ plasma levels also decayed rapidly with mean terminal phase half-lives of 0.77-0.85 h.
Although undetectable prior to dose 5 in most patients (26/32), mean Cmax values of PCZ were significantly greater (3.7-5.8 fold) than on day 1 at each dose level.
Preliminary data indicates that all 3 metabolites achieved higher plasma concentrations than PCZ and were eliminated more slowly.

Conclusion. Despite being in clinical use for more than 30 years, this study represents the first attempt to examine the PK of PCZ in humans using specific and sensitive analytical methods.
Alterations in its PK upon repeated daily dosing appear to result from decreased drug elimination, possibly due to an inhibition of hepatic metabolism by PCZ itself or products of its metabolism, rather than an effect on the rate or extent of absorption.
These observations may have important implications on the clinical use of this drug.

© Copyright 2002 American Society of Clinical Oncology