Estimation of pharmacokinetic parameters
Dr. N. Holländer , FDM, Institute of Medical Biometry and Medical Informatics
PD Dr. K. Mross, Department of Medical Oncology, Tumorbiology Center Freiburg
Prof. Dr. M. Schumacher, FDM, Institute of Medical Biometry and Medical Informatics
Prof. Dr. H. Maier-Lenz, Center for Clinical Studies, University Hospital Freiburg
- Actual ad future projects
Based on a two-compartment model the elimination of a drug from the plasma (central compartment) can be described by a biexponential function. Assuming a specific model with respect to the variability of the observed drug concentrations, weighted nonlinear least squares regression is used in order to estimate the parameters of the biexponential function. The weights that also influence the estimation of the resulting pharmacokinetic parameters are often chosen according to the constant coefficient of variation model, i.e. assuming a proportional increase of the variability with increasing dose. However, this assumption seems not to be proven in many applications. We have shown that the estimation of pharmacokinetic parameters may depend strongly on the choosen weights and propose a simple method to use information on the underlying analytical method (e.g. HPLC) in order to find the most appropriate weighting scheme (1). The methodology has been applied to a phase I study on the use of paclitaxel in cancer patients (2,3). In a further study, we compare the pharmacokinetics of a paclitaxel 1-hour versus 3-hour infusion (4). The data are taken from a randomized contolled clinical trial.
In many applications - usually phase I clinical trials - the results for individual patients are aggregated in order to describe the pharmacokinetics in the patient's population. This ad hoc approach will be compared to the more sophisticated random effects models used in population pharmacokinetics. Using the data of the phase I study with paclitaxel, both methods lead to similar results (Diploma thesis by F. Weiss, Dortmund). However, further work is necessary to investigate both approaches in more detail.
- Publications
The influence of different weighting schemes on the calculation of pharmacokinetic parameters for paclitaxel, [FDM-Preprint No. 50, ps.gz, 136k]
(2) Maier-Lenz H, Hauns B, Häring B, Koetting J, Mross K, Unger C,
Bauknecht T, Du Bois A, Meerpohl HG, Holländer N, Diergarten K
Phase I study of paclitaxel administered as a 1-hour infusion:
Toxicity and pharmacokinetics,
Seminars in Oncology, 24, No. 6 Suppl 19, 1997, 16-9
(3) Mross K, Holländer N, Hauns B, Schumacher M, Maier-Lenz H
The pharmacokinetics of a 1-h paclitaxel infusion,
Cancer Chemotheraoy and Pharmacology, 45, 2000, 463-70
(4) Mross K, Häring B, Holländer N, Mielke S, Behringer D, Massing U, Unger C
Comparison of 1-hour and 3-hours Paclitaxel infusion pharamocokinetics:
Results from a randomized trial,
Onkologie, 25, 2002, 503-508