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Clinical Investigations |
Departments of Neurological Surgery (M.D.P., S.M.C.) and Neuro-Oncology (M.K.N.), University of California at San Francisco, San Francisco, CA 94143; Departments of Neuro-Oncology (W.K.A.Y.) and Biostatistics (K.R.H.), The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Departments of Neurology and Hematology/Oncology, Mayo Clinic Jacksonville, Jacksonville, FL 32224 (K.A.J.); Departments of Medicine (H.I.R.) and Radiotherapy (M.P.M.), University of Wisconsin, Madison, WI 53792; Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD 20892 (H.A.F.); Center for Neuro-Oncology, Dana Farber Cancer Institute, Boston, MA 02115 (P.Y.W.); Neuro-Oncology Program, University of California, Los Angeles, Los Angeles, CA 90095 (T.F.C.); Division of Neuro-Oncology, University of Virginia Health Science Center, Charlottesville, VA 22908 (D.S.); Department of Neurology, University of Michigan, Ann Arbor, MI 48109 (H.S.G., L.J.); Department of Neurology, The University of Texas Southwestern Medical Center, Dallas, TX 75390 (K.L.F.); College of Pharmacy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229 (J.K.); USA
2 Address correspondence to Michael Prados, University of California at San Francisco, 400 Parnassus Avenue, Room A808, San Francisco, CA 94143-0372, USA (pradosm{at}neurosurg.ucsf.edu).
Abstract
This study was conducted to determine the maximum tolerated dose and dose-limiting toxicity of irinotecan (CPT-11) administered every 3 weeks to adults with progressive malignant glioma who were treated with enzyme-inducing antiepileptic drug (EIAED) therapy, and to compare the pharmacokinetics with those in patients not on EIAED therapy treated at the recommended phase 2 dose for other cancers. The CPT-11 dose was 350 mg/m2 i.v. every 3 weeks and remained fixed in patients not on EIAED therapy, but the dose was escalated by 50-mg/m2 increments in patients on EIAED therapy. CPT-11 and its metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (7-ethyl-10[4-N-(5 aminopentanoic acid)-1-piperidine]carbonyloxycamptothecin) were characterized in both groups. Patients on EIAEDs received 350 to 800 mg/m2 of CPT-11. Dose-limiting toxicity was due to grade 3 diarrhea despite maximal doses of loperamide. The systemic levels of CPT-11, APC, SN-38G, and SN-38 were all lower in the EIAED group. There was a moderate-to-fair relationship between CPT-11 dose and the area under the curve (AUC) for CPT-11 and APC over the dosage range of 350 to 800 mg/m2, but no relationship between CPT-11 dose and the AUC for SN-38 or SN-38G. At the 750-mg/m2 dose, the AUC for CPT-11 (21.6 µg x h/ml) matched the AUC (21.6 µg x h/ml) in the non-EIAED group treated with 350 mg/m2 of CPT-11. We conclude that the recommended phase 2 dose of CPT-11 for patients on EIAEDs is 750 mg/m2 when given every 3 weeks. A phase 2 study of patients with recurrent malignant glioma is ongoing to assess the efficacy of CPT-11 when the dose is stratified according to the use of EIAEDs.
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