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

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^TM 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 C_max was greater than 350 µg l⁻¹. This cut‐off concentration closely corresponded to the IC₅₀ of a sigmoidal E_max 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 (C_max > 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.

DOI: 10.1046/j.1365-2125.2003.01826.x

View this article

• Full article (html)
• Enhanced article (html)
• PDF
• References