Docetaxel and ketoconazole in advanced hormone-refractory prostate carcinoma: a phase I and pharmacokinetic study.
BACKGROUND
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.


METHODS
For all initial patients, docetaxel was administered intravenously at a dose of 55 mg/m(2) over 1 hour every 21 days. Starting on Day 8 after their first docetaxel dose, cohorts of at least 3-5 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).


RESULTS
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/m(2). 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.


CONCLUSIONS
The recommended Phase II dose for this combination is ketoconazole 400 mg twice daily and docetaxel 55 mg/m(2) every 21 days.
Van Veldhuizen
Peter J
PJ
Department of Medicine, Section of Hematology/Oncology, Kansas City Veterans Affairs Medical Center, University of Kansas Medical Center, Kansas City, Missouri 64128, USA. peter.vandeldhuizen@med.va.gov
Reed
Gregory
G
Aggarwal
Arvind
A
Baranda
Joaquina
J
Zulfiqar
Muhammad
M
Williamson
Stephen
S
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D043823:Taxoids; D016896:Treatment Outcome
D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel; D007654:Ketoconazole