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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 (Cmax) 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 Cmax 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
Source:
http://www.asco.org/ac/1,1003,_12-002324-00_18-002002-00_19-002086-00_29-00A-00_42-00ONeill-00_43-00-00_44-00-00_45-00
Author-00_46-00Title-00_47-00Title-00_48-00and-00_49-00and,00.asp?cat=CNS+Tumors&parent=CENTRAL+NERVOUS+SYSTEM+TUMORS
&returnpid=2323 |
