Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Grossman, S.A. et al.

Grossman, Carson, Batchelor, Lesser, Mikkelsen, Alavi, Phuphanich, Hammour, Fisher, Supko,

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

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.[1]

References

The effect of enzyme-inducing antiseizure drugs on the pharmacokinetics and tolerability of procarbazine hydrochloride. Grossman, S.A., Carson, K.A., Batchelor, T.T., Lesser, G., Mikkelsen, T., Alavi, J.B., Phuphanich, S., Hammour, T., Fisher, J.D., Supko, J.G. Clin. Cancer Res. (2006) [Pubmed]

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