Population Pharmacokinetic Model for Cremophor EL
A. Henningsson(1), A. Sparreboom(2,3), W. J. Loos(3), J. Verweij(3), M. Silvander(4,5) and M. O. Karlsson(1)
(1)Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden, (2)Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, Md, USA, (3)Department of Medical Oncology, Erasmus MC – Daniel den Hoed Cancer Center, Rotterdam, the Netherlands, (4)Department of Physical Chemistry, Uppsala University, Uppsala, Sweden, (5)Formulation Development, BioAgri AB, Uppsala, Sweden
Objectives: The pharmacologically active micelle-forming vehicle Cremophor EL (CrEL) has been shown to affect the pharmacokinetics of paclitaxel after Taxol® administrations[1]. CrEL micelle entrapment of paclitaxel within the plasma has been suggested as the primary underlying mechanism. The pharmacokinetics of CrEL has been shown to be schedule dependent and capacity limited elimination within the plasma has been suggested[2]. The aim of this study was to develop a population pharmacokinetic model that could describe and predict CrEL plasma concentrations after Taxol® administration and to investigate the critical aggregation concentration (CAC) in human plasma in vitro.
Patients and Methods: The learning data included 147 CrEL concentration-time profiles obtained from 116 patients receiving 1-, 3- or 24-hour infusions of Taxol®. CrEL concentrations were measured with a Coomassie Brilliant Blue G-250 colorimetric dye-binding assay[3, 4]. The population pharmacokinetic analysis was performed in NONMEM. A validation data set with 45 individuals receiving 3-hour infusions of Taxol® was used to investigate the predictive performance of the model. The apparent CAC was estimated by observing changes in plasma surface tension determined with a droplet weight method[5], 1, 3 and 24 hours after addition of CrEL/EtOH/NaCl or Taxol®.
Results: A three-compartment model with capacity limited elimination with an additional linear elimination pathway as well as a separate volume of distribution for the 24-hour infusion schedule were required to describe all data of the learning data set. Body surface area was statistically significant (P<0.001) as covariate on maximal elimination rate, volume of distribution of the central compartment and one of the peripheral compartments. The population model could adequately describe the concentrations of the validation data set where the prediction errors were similar as for the learning data. A previously published population pharmacokinetic model[2], based on CrEL concentrations measured with another assay than the one used here, could not adequately describe our data. The apparent CAC in plasma was 0.39 mL/L, a concentration exceeded after Taxol® administrations in patients, suggesting that CrEL form aggregates in vivo.
Conclusions: The population model developed on the present data could adequately predict and describe the CrEL concentrations after Taxol® administrations. This model could be most useful when no CrEL concentration data is available and population pharmacokinetic models for paclitaxel including CrEL concentrations will be used.
References:
[1] Henningsson, A., et al., Mechanism-based pharmacokinetic model for paclitaxel. J Clin Oncol, 2001. 19(20): p. 4065-73.
[2] van den Bongard, H.J., et al., A population analysis of the pharmacokinetics of Cremophor EL using nonlinear mixed-effect modelling. Cancer Chemother Pharmacol, 2002. 50(1): p. 16-24.
[3] Brouwer, E., et al., Linearized colorimetric assay for cremophor EL: application to pharmacokinetics after 1-hour paclitaxel infusions. Anal Biochem, 1998. 261(2): p. 198-202.
[4] Sparreboom, A., et al., Quantitation of Cremophor EL in human plasma samples using a colorimetric dye-binding microassay. Anal Biochem, 1998. 255(2): p. 171-5.
[5] Tornberg, E., A surface tension apparatus according to the drop volume principle. Journal of Colloid and Interface Science, 1977. 60(1): p. 50-59.