A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator, Zosuquidar Trihydrochloride (LY335979)

Abstract

Aims: To develop a population pharmacokinetic model for paclitaxel in the presence of a MDR modulator, zosuquidar 3HCl. Methods: The population approach was used (implemented with NONMEM) to analyse paclitaxel pharmacokinetic data from 43 patients who received a 3-h intravenous infusion of paclitaxel (175 mg m-2 or 225 mg m-2) alone in cycle 2 or concomitantly with the oral administration of zosuquidar 3HCl in cycle 1. Results: The structural pharmacokinetic model for paclitaxel, accounting for the Cremophor EL™ impact, was a three-compartment model with a nonlinear model for paclitaxel plasma clearance (CL), involving a linear decrease in this parameter during the infusion and a sigmoidal increase with time after the infusion. The final model described the effect of Zosuquidar 3HCl on paclitaxel CL by a categorical relationship. A 25% decrease in paclitaxel CL was observed, corresponding to an 1.3-fold increase in paclitaxel AUC (from 14829 μg l-1 h to 19115 μg l-1 h following paclitaxel 175 mg m-2) when zosuquidar Cmax was greater than 350 μg l-1. This cut-off concentration closely corresponded to the IC50 of a sigmoidal Emax relationship (328 μg l-1). A standard dose of 175 mg m-2 of paclitaxel could be safely combined with doses of zosuquidar 3HCl resulting in plasma concentrations known, from previous studies, to result in maximal P-gp inhibition. Conclusions: This analysis provides a model which accurately characterized the increase in paclitaxel exposure, which is most likely to be due to P-gp inhibition in the bile canaliculi, in the presence of zosuquidar 3HCl (Cmax >350 μg l-1) and is predictive of paclitaxel pharmacokinetics following a 3 h infusion. Hence the model could be useful in guiding therapy for paclitaxel alone and also for paclitaxel administered concomitantly with a P-gp inhibitor, and in designing further clinical trials.