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- Title
Docetaxel and ketoconazole in advanced hormone-refractory prostate carcinoma(This article is a U.S. Government work and, as such, is in the public domain in the United States of America.)The views expressed herein do not necessarily reflect the views of the Department of Veterans Affairs or the U.S. Government.)
- Authors
Peter J. Van Veldhuizen; Gregory Reed; Arvind Aggarwal; Joaquina Baranda; Muhammad Zulfiqar; Stephen Williamson
- Abstract
Docetaxel has significant single-agent activity in patients with prostate carcinoma, and ketoconazole has activity as a second-line hormonal agent. In vitro, ketoconazole exhibits synergy with several chemotherapeutic agents. A potential drug interaction exists, however, because both docetaxel and ketoconazole are metabolized hepatically by the cytochrome p450 system (CYP3A4). The authors performed a Phase I study and a pharmacokinetic study evaluating the both tolerability of a docetaxel/ketoconazole combination as well as this potential drug interaction. For all initial patients, docetaxel was administered intravenously at a dose of 55 mg/m2 over 1 hour every 21 days. Starting on Day 8 after their first docetaxel dose, cohorts of at least 35 new patients were enrolled to receive escalating doses of ketoconazole. When the maximally tolerated dose (MTD) of ketoconazole was reached, the subsequent cohort of patients received an escalating dose of docetaxel. Pharmacokinetic studies were performed after docetaxel infusions on Day 1 (prior to ketoconazole) and Day 22 (after starting ketoconazole). Twenty-six patients were enrolled and completed at least 2 cycles of treatment. The MTD was ketoconazole 400 mg twice daily and docetaxel 55 mg/m2. Dose-limiting toxicities included neutropenia and fatigue. Ketoconazole did not cause a consistent effect on docetaxel pharmacokinetics, although there was significant intrapatient and interpatient variability in serum levels. The recommended Phase II dose for this combination is ketoconazole 400 mg twice daily and docetaxel 55 mg/m2 every 21 days. Cancer 2003. Published 2003 by the American Cancer Society.
- Subjects
DOCETAXEL; KETOCONAZOLE; PIPERAZINE; DRUG interactions; CYTOCHROMES
- Publication
Cancer (0008543X), 2003, Vol 98, Issue 9, p1855
- ISSN
0008-543X
- Publication type
Article