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at time of writing, BS, Pre-doctoral Fellow, Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, MD; now, Research Associate, Division of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
at time of writing, Fellow, Clinical Pharmacology Research Core, National Cancer Institute; now, Assistant Professor, Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore
at time of writing, Fellow, Clinical Pharmacology Research Core, National Cancer Institute; now, Director, Clinical Research Unit, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Senior Scientist, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, Frederick, MD
at time of writing, Coordinator, Developmental Therapeutics Program, Clinical Trials Unit, National Cancer Institute; now, Chief, Molecular Therapeutics Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Bethesda
Research Nurse, Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute
at time of writing, Section Chief, Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute; now, Vice President and Global Head, Oncology Therapeutic Area, Aventis Pharmaceuticals, Bridgewater, NJ
Clinical Fellow, Clinical Pharmacology Research Core, National Cancer Institute
Senior Investigator, Investigational Drug Branch, Cancer Therapy and Evaluation Program, National Cancer Institute
Associate Director, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute
Senior Investigator, Head, Molecular Pharmacology Section, Cancer Therapeutics Branch; Head, Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit, National Cancer Institute
Reprints: William D Figg PharmD, Molecular Pharmacology Section, Cancer Therapeutics Branch; Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit, National Cancer Institute, Bldg. 10, Rm. 5A01, MSC1910, 9000 Rockville Pike, Bethesda, MD 20892-1906, FAX 301/402-8606, wdfigg{at}helix.nih.gov
BACKGROUND: Flavopiridol, a novel flavone derivative, inhibits cyclin-dependent kinase-1. We initiated a Phase I trial in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile.
OBJECTIVE: To characterize the clinical pharmacology of flavopiridol.
METHODS: Serial plasma samples were collected and analyzed by HPLC using electrochemical detection. The pharmacokinetics were analyzed by noncompartmental analysis. Enterohepatic recirculation was studied by analyzing fecal samples, with an attempt to correlate cholecystokinin and post-infusional peak concentrations. The plasma protein binding was studied using equilibrium dialysis.
RESULTS: Seventy-six patients were treated with flavopiridol at 13 dose levels for a total of 504 cycles of treatment. The average steady-state concentration was 26.5 and 253 nM at 4 and 122.5 mg/m2, respectively. The clearance ranged from 49.9 to 2943 mL/min, with nonlinearity at doses >50 mg/m2/d. A post-infusional increase in plasma flavopiridol concentrations was noted in a subset of patients and generally occurred between 3 and 24 hours after the end of infusion. Flavopiridol was found in fecal matter, suggesting enterohepatic recirculation. There was nonsaturable plasma protein binding of flavopiridol (fu = 6%).
CONCLUSIONS: The dose-limiting toxicity for the Phase I trial of flavopiridol was secretory diarrhea. We failed to identify a clear relationship between dose or concentration and diarrhea. At 50 and 78 mg/m2/d, the mean steady-state plasma concentrations were 278 and 390 nM. These concentrations were well above those noted for in vitro antiproliferative activity. Nonlinear elimination was observed at doses above 50 mg/m2/d, and postinfusional peaks appear to be related to enterohepatic recirculation.
Key Words: cancer, flavopiridol, pharmacology
Published Online, August 8, 2003. www.theannals.com, DOI 10.1345/aph.1C404
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