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Phase I and Pharmacokinetic Study of Oral Paclitaxel

From the Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, and Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam; Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; and Baker Norton Pharmaceuticals, Miami, FL.

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

PURPOSE: To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT).

PATIENTS AND METHODS: A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg/m² as a 3-hour infusion.

RESULTS: The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg/m². Dose escalation of oral paclitaxel from 60 to 300 mg/m² resulted in significant but less than proportional increases in the plasma area under the concentration-time curve (AUC) of paclitaxel. The mean AUC values ± SD after 60, 180, and 300 mg/m² of oral paclitaxel were 1.65 ± 0.93, 3.33 ± 2.39, and 3.46 ± 1.37 µmol/L·h, respectively. Dose increment and scheduling of CsA did not result in a further increase in the AUC of paclitaxel. The AUC of intravenous paclitaxel was 15.39 ± 3.26 µmol/L·h.

CONCLUSION: The MTD of oral paclitaxel was 300 mg/m². However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg/m², the oral paclitaxel dose of 180 mg/m² in combination with 15 mg/kg oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good.

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