Population pharmacokinetics of orally administered paclitaxel formulated in Cremophor EL

Abstract

AimThe 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. MethodPaclitaxel 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. ResultsAfter absorption, paclitaxel pharmacokinetics were best described using a twocompartment model with linear distribution from the central compar tment 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 paclita xel 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. ConclusionA 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.

A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer

“…It was previously described by us that CrEL limits the absorption rate of paclitaxel due to encapsulation in CrEL micelles. As the concentration of CrEL in the gastrointestinal tract decreases with time due to distribution, breakdown and elimination of CrEL, more unbound paclitaxel becomes available for absorption in the systemic circulation with time and consequently the absorption rate increases (de Jonge et al, 2005). The lower T max after oral SMEOF#3 is probably due to the ability of the SMEOF#3 formulation to remain stable in the gastrointestinal tract avoiding precipitation of paclitaxel leading to a major fraction of paclitaxel in solution, which is available for absorption.…”

Supersaturated polymeric micelles for oral cyclosporine A delivery

“…The loading of risperidone into PEG-b-P(CL-co-TMC) micelles did not improve its permeability across Caco-2 monolayer [10]. Moreover, in some cases, PMs have been found to impede the absorption of hydrophobic drugs [11,12]. For example, Cremophor EL micelles have been shown to impair absorption of paclitaxel [12].…”

“…Moreover, in some cases, PMs have been found to impede the absorption of hydrophobic drugs [11,12]. For example, Cremophor EL micelles have been shown to impair absorption of paclitaxel [12]. The gastrointestinal absorption of highly lipophilic compounds from PMs is largely related to the 0939-6411/$ -see front matter Crown Copyright Ó 2013 Published by Elsevier B.V. All rights reserved.…”

The Effect of Novel Surfactants and Solutol® HS 15 on Paclitaxel Aqueous Solubility and Permeability Across a Caco-2 Monolayer

“…Few studies have been performed to evaluate the oral bioavailability of paclitaxel and of those, all clinical studies to determine the oral bioavailability have used the commercially available IV formulation, containing CrEL® 16. The vehicle CrEL® has been shown to impair the absorption of paclitaxel by micellar entrapment of the drug in the gastrointestinal (GI) tract, resulting in decreased oral bioavailability of the drug 16, 17. It also has been shown in patients that the absorption of the orally administered paclitaxel is increased by co‐administration of cyclosporine A, which is an alternate substrate for P‐gp and cytochrome P‐450 isozyme 3A (CYP3A4) 18, 19.…”