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Coadministration of Cyclosporine Strongly Enhances the Oral Bioavailability of Docetaxel

From the Department of Medical Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht; and Department of Internal Medicine, Medisch Spectrum Twente, Enschede, the Netherlands.

Address reprint requests to Mirte M. Malingré, Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slo-tervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands; email: apmmg{at}slz.nl

PURPOSE: Oral bioavailability of docetaxel is very low, which is, at least in part, due to its affinity for the intestinal drug efflux pump P-glycoprotein (P-gp). In addition, metabolism of docetaxel by cytochrome P450 (CYP) 3A4 in gut and liver may also contribute. The purpose of this study was to enhance the systemic exposure to oral docetaxel on coadministration of cyclosporine (CsA), an efficacious inhibitor of P-gp and substrate for CYP 3A4.

PATIENTS AND METHODS: A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral docetaxel 75 mg/m² with or without a single oral dose of CsA 15 mg/kg. CsA preceded oral docetaxel by 30 minutes. During subsequent courses, patients received intravenous (IV) docetaxel 100 mg/m².

RESULTS: The mean (± SD) area under the concentration-time curve (AUC) in patients who received oral docetaxel 75 mg/m² without CsA was 0.37 ± 0.33 mg·h/L and 2.71 ± 1.81 mg·h/L for the same oral docetaxel dose with CsA. The mean AUC of IV docetaxel 100 mg/m² was 4.41 ± 2.10 mg·h/L. The absolute bioavailability of oral docetaxel was 8% ± 6% without and 90% ± 44% with CsA. The oral combination of docetaxel and CsA was well tolerated.

CONCLUSION: Coadministration of oral CsA strongly enhanced the oral bioavailability of docetaxel. Interpatient variability in the systemic exposure after oral drug administration was of the same order as after IV administration. These data are promising and form the basis for the further development of a clinically useful oral formulation of docetaxel.

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