Phase I and pharmacokinetic study of oral paclitaxel

Purpose: To investigate dose escalation of oral paclitaxel in combination w ith dose increment and scheduling of cyclosporine (CsA) to improve the syst emic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT). Patients and Methods: A fetal of 53 patients received, on one occasion, ora l paclitaxel in combination with CsA, coadministered to enhance the absorpt ion of paclitaxel, and, on another occasion, intravenous paclitaxel at a. d ose of 175 mg/m(2) 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 revel of 360 mg/m( 2). Dose escalation of oral paclitaxel from 60 to 300 mg/m(2) resulted in s ignificant but less than proportional increases in the plasma area under th e concentration time curve (AUC) of paclitaxel. The mean AUC values +/- SD after 60, 180, and 300 mg/m(2) of oral paclitaxel were 1.65 +/- 0.93, 3.33 +/- 2.39, and 3.46 +/- 1.37 mu mol/L.h, respectively. Dose increment and sc heduling of CsA did not result in a further increase in the AUC of paclitax el. The AUC of intravenous paclitaxel was 15.39 +/- 3.26 mu mol/L.h. Conclusion: The MTD of oral paclitaxel was 300 mg/m(2). However, because th e pharmacokinetic data of oral paclitaxel, in particular at the highest dos es applied, revealed nonlinear pharmacokinetics with only a moderate furthe r increase of the AUC with doses up to 300 mg/m(2), the oral paclitaxel dos e of 180 mg/m(2) in combination with 15 mg/kg oral CsA is considered most a ppropriate for further investigation. The safety of the oral combination at this dose level was good. J Clin Oncol 18:2468-2475. (C) 2000 by American Society of Clinical Oncology.