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

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Abstract

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/m2, 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/m2 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.

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Acknowledgments

We would like to thank NHG small innovative grant and MAP-RISE program for their support of the study.

Conflict of interest

All authors express no conflicts of interest in this work.

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Authors and Affiliations

  1. Cancer Therapeutics Research Group, Department of Haematology-Oncology, National University Hospital, 5 Lower Kent Ridge Road, Singapore, Singapore, 119074

    Wei-Peng Yong, Ling-Zhi Wang, Lai-San Tham, Chiung-Ing Wong, Soo-Chin Lee, Ross Soo, Norita Sukri & Boon-Cher Goh

  2. Department of Pharmacology, National University of Singapore, Singapore, Singapore, 119074

    Ling-Zhi Wang, How-Sung Lee & Boon-Cher Goh

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  1. Wei-Peng Yong
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Correspondence to Boon-Cher Goh.

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Yong, WP., Wang, LZ., Tham, LS. et al. A phase I study of docetaxel with ketoconazole modulation in patients with advanced cancers. Cancer Chemother Pharmacol 62, 243–251 (2008). https://doi.org/10.1007/s00280-007-0598-1

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  • DOI: https://doi.org/10.1007/s00280-007-0598-1

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