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

• Published in: Clinical cancer research Vol. 12; no. 17; pp. 5174 - 5181
• Main Authors: GROSSMAN, Stuart A, CARSON, Kathryn A, BATCHELOR, Tracy T, LESSER, Glenn, MIKKELSEN, Tom, ALAVI, Jane B, PHUPHANICH, Surasak, HAMMOUR, Tarek, FISHER, Joy D, SUPKO, Jeffrey G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2006
• Subjects: Administration, Oral; Adult; Aged; Anticonvulsants - administration & dosage; Anticonvulsants - pharmacology; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Brain cancer; cancer therapy; Cohort Studies; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; drug interactions; Enzyme Induction - drug effects; Female; Follow-Up Studies; glioblastoma multiforme; Glioma - drug therapy; Glioma - enzymology; human; Humans; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Procarbazine - administration & dosage; Procarbazine - adverse effects; Procarbazine - pharmacokinetics; Spectrometry, Mass, Electrospray Ionization - methods; Time Factors; Treatment Outcome; Antineoplastic agent; Drug; Procarbazine; Alkylating agent; Hydrochlorides; Enzyme; Toxicity; Pharmacokinetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0932

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/m 2 /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/m 2 /d for the +EIASD group and the highest dose evaluated in −EIASD patients was 334 mg/m 2 /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.