| Clinical pharmacology of flavopiridol following a 72-hour continuous infusion. | |
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MedLine Citation:
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PMID: 14519054 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Michelle A Rudek; Kenneth S Bauer; Richard M Lush; Sherman F Stinson; Adrian M Senderowicz; Donna J Headlee; Susan G Arbuck; Michael C Cox; Anthony J Murgo; Edward A Sausville; William D Figg |
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Publication Detail:
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Type: Clinical Trial; Clinical Trial, Phase I; Journal Article |
Journal Detail:
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Title: The Annals of pharmacotherapy Volume: 37 ISSN: 1060-0280 ISO Abbreviation: Ann Pharmacother Publication Date: 2003 Oct |
Date Detail:
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Created Date: 2003-10-01 Completed Date: 2004-02-26 Revised Date: 2004-11-17 |
Medline Journal Info:
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Nlm Unique ID: 9203131 Medline TA: Ann Pharmacother Country: United States |
Other Details:
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Languages: eng Pagination: 1369-74 Citation Subset: IM |
Affiliation:
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Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, MD, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Diarrhea / chemically induced, complications Feces / chemistry Female Flavonoids / administration & dosage*, metabolism, pharmacokinetics* Food Humans Infusions, Intravenous Male Maximum Tolerated Dose Middle Aged Neoplasms / drug therapy Pharmacology, Clinical* Piperidines / administration & dosage*, metabolism, pharmacokinetics* Protein Binding / drug effects Time Factors |
| Chemical | |
Reg. No./Substance:
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0/Flavonoids; 0/Piperidines; 146426-40-6/flavopiridol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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