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  • Title: A population analysis of the pharmacokinetics of Cremophor EL using nonlinear mixed-effect modelling.
    Author: van den Bongard HJ, Mathôt RA, van Tellingen O, Schellens JH, Beijnen JH.
    Journal: Cancer Chemother Pharmacol; 2002 Jul; 50(1):16-24. PubMed ID: 12111107.
    Abstract:
    PURPOSE: The purpose of this study was to develop a population pharmacokinetic model for Cremophor EL used as a formulation vehicle for paclitaxel. METHODS: Plasma concentration-time data from 70 patients (85 courses) treated with paclitaxel dissolved in Cremophor EL were used. The nonlinear mixed-effect modelling (NONMEM) program was used for the population pharmacokinetic analysis. The influence of patient characteristics on the pharmacokinetics of Cremophor EL was determined. The stability of the final model was evaluated using bootstrapping. RESULTS: The data were optimally fitted to a three-compartment model with Michaelis-Menten elimination from the central compartment. The following pharmacokinetic parameters were estimated: volume of the central compartment (V1=2.59 l), volumes of two peripheral compartments (V2=1.81 l, V3=1.61 l), intercompartmental clearance between central and peripheral compartments (Q12=1.44 l/h, Q13=0.155 l/h), maximal elimination rate (Vmax=0.193 ml/h), and concentration at half Vmax (Km=0.122 ml/l). Interindividual variability of the pharmacokinetic parameters was quantified for V1 (25%), V2 (36%) and Vmax (31%). Residual variability consisted of a combined additional (0.095 ml/l) and proportional error (7%). Gender, body surface area and performance status according to the World Health Organization were significantly correlated with V1, V2 and Vmax, respectively ( P<0.0001). The median parameter estimates of 1000 bootstrap samples were in accordance with those obtained with the original data set, indicating the validity of the population model. CONCLUSIONS: The population model was able to adequately describe the pharmacokinetic parameters and influence of covariates on the pharmacokinetics of Cremophor EL. This model can be used when studying the relationship between the pharmacokinetics and toxicity of Cremophor EL, and the drug's influence on the pharmacokinetics of paclitaxel.
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