SAN ANTONIOEnzyme-inducing antiepileptic drugs (EIAEDs) can
significantly alter the metabolism of irinotecan (Camptosar) and should be
taken into consideration when treating patients for brain tumors, according to
John G. Kuhn, PharmD. Dr. Kuhn is professor of Pharmacology and Medicine at the
University of Texas Health Sciences Center in San Antonio, Texas. He discussed
data on irinotecan pharmacokinetics from an ongoing North American Brain Tumor
Consortium (NABTC) phase I study.
Irinotecan is metabolized via CYP3A4 to less active oxidative metabolites
and bioactivated in the liver and intestine by carboxylesterases to the active
SN-38 metabolite. Dr. Kuhn said the NABTC study was designed to determine the
maximum tolerated dose of irinotecan given every 3 weeks to patients who were
taking EIAEDs and to patients who were not taking such drugs. A phase II study
will determine efficacy in progressive or recurrent primary gliomas.
Inducing and Noninducing Drugs Are Tested
The EIAEDs include phenytoin (Dilantin), phenobarbital (Donnatal), and
carbamazepine (Tegretol). The noninducing AEDs include gabapentin (Neurontin),
valproic acid (Depakene), levetiracetam (Keppra), topiramate (Topamax),
lamotrigine (Lamictal), zonisamide (Zonegran), and tiagabine (Gabitril).
Patients not on EIAEDs (n = 34, 22 evaluable) were treated with irinotecan 350
mg/m² IV over 90 minutes with no dose escalations. Patients on EIAEDs (n = 48,
34 evaluable) were treated with irinotecan at 350 mg/m² with dose escalations
in 50 mg/m² increments.
"In the EIAEDs group, the dose-limiting toxicity was grade 3 diarrhea
at the 800 mg/m² dose level. The phase II dose will be 750 mg/m² every 3 weeks.
Clearance of irinotecan was about twofold higher in patients taking these
drugs, and there was a dramatic decrease in the level of the active metabolite
SN-38," Dr. Kuhn said. "Non-EIAEDs with or without steroids had
little effect on irinotecan metabolism and excretion. Gabapentin, although not
an enzyme-inducing agent, had a greater than expected effect on irinotecan