Population pharmacokinetics of orally administered paclitaxel formulated in Cremophor EL

Aim: The vehicle Cremophor EL (CrEL) has been shown to impair the absorption of paclitaxel by micellar entrapment of the drug in the gastrointestinal tract. The goal of this study was to develop a semimechanistic population pharmacokinetic model to study the influence of CrEL on the oral absorption of paclitaxel. Method: Paclitaxel plasma-concentration time profiles were available from 55 patients (M:F, 17:38; total 67 courses; 797 samples), receiving paclitaxel orally once or twice daily (dose range 60-360 mg m ^-2) together with 12-15 mg kg^-1 cyclosporin A. A population pharmacokinetic model was developed using the nonlinear mixed effect modelling program NONMEM. Results: After absorption, paclitaxel pharmacokinetics were best described using a two-compartment model with linear distribution from the central compartment into a peripheral compartment and first-order elimination. Paclitaxel in the gastrointestinal tract was modelled as free fraction or bound to CrEL, with only the free fraction available for absorption into the central compartment. The equilibrium between free and bound paclitaxel was influenced by the concentration of CrEL present in the gastrointestinal tract. The concentration of CrEL in the gastrointestinal tract decreased with time with a first order rate constant of 1.73 h^-1. The bioavailability of paclitaxel was independent of the dose and of CrEL. Estimated apparent paclitaxel clearance and volume of distribution were 127 l h ^-1 and 409 l, respectively. Large interpatient variability was observed. Covariate analysis did not reveal significant relationships with any of the pharmacokinetic parameters. Conclusion: A pharmacokinetic model was developed that described the pharmacokinetics of orally administered paclitaxel. CrEL strongly influenced paclitaxel absorption from the gastrointestinal tract resulting in time-dependent but no significant dose-dependent absorption over the examined dose range studied.