A phase I study of docetaxel with ketoconazole modulation in patients with advanced cancers

• Published in: Cancer chemotherapy and pharmacology Vol. 62; no. 2; pp. 243 - 251
• Main Authors: Yong, Wei-Peng, Wang, Ling-Zhi, Tham, Lai-San, Wong, Chiung-Ing, Lee, Soo-Chin, Soo, Ross, Sukri, Norita, Lee, How-Sung, Goh, Boon-Cher
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-07-2008; Springer; Springer Nature B.V
• Subjects: Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cancer Research; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Female; Humans; Ketoconazole - administration & dosage; Ketoconazole - adverse effects; Ketoconazole - pharmacokinetics; Ketoconazole - therapeutic use; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Midazolam - administration & dosage; Midazolam - pharmacokinetics; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - pathology; Neutropenia - chemically induced; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Taxoids - administration & dosage; Taxoids - pharmacokinetics; Taxoids - therapeutic use; CYP3A; Midazolam; Ketoconazole; Pharmacokinetic; Docetaxel; Antineoplastic agent; Human; Imidazole derivatives; Enzyme; Isozyme; Cytochrome P450; Malignant tumor; Docetaxel . Ketoconazole; Treatment; Midazolam . Pharmacokinetic; Taxane derivatives; Modulation; Phase I trial; Benzodiazepine derivatives; Advanced stage; Pharmacokinetics; Antimitotic; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-007-0598-1

Purpose
The aims were to determine the maximum tolerable dose (MTD) of docetaxel with CYP3A inhibition by ketoconazole, and to correlate the pharmacokinetics of docetaxel with midazolam phenotyping of CYP3A activity.
Methods
Forty-one patients with refractory metastatic cancers were treated with an escalating dose of intravenous docetaxel once in every 3 week of 10 mg/m
2
, concurrently with oral ketoconazole 200 mg twice daily for 3 days starting 2 days before the administration of docetaxel. Midazolam phenotyping test with ketoconazole modulation was performed before the first cycle of docetaxel. Docetaxel and midazolam pharmacokinetics were compared to our previous study of docetaxel treatment without ketoconazole modulation.
Results
Neutropenia was the dose-limiting toxicity. The maximum tolerated dose was 70 mg with mean AUC at 70 mg similar to 75 mg/m
2
of docetaxel without ketoconazole. The plasma clearances of docetaxel and midazolam were reduced by 1.7- and 6-fold, respectively. The variability of midazolam AUC was reduced from 157 to 67%, but variability of docetaxel clearance was not reduced by CYP3A inhibition. Docetaxel clearance correlated with renal function and maximum concentration of ketoconazole, but not midazolam clearance or other variables of hepatic function.
Conclusion
Fixed dosing was found to be feasible, without increased variability of clearance or neutrophil toxicity compared to BSA-based dosing. With ketoconazole modulation, docetaxel clearance correlated with renal function but not CYP3A phenotype.