ANALYSIS OF PSEUDO-PROFILES IN ORGAN PHARMACOKINETICS AND TOXICOKINETICS

In general, the pharmacokinetic model parameters, like rate constants, area under the curve (AUG) etc. are estimated via a two-stage procedu re, where the values obtained from concentration-time relationships wi thin one subject (experimental unit) are considered to be functionally related to the drug concentrations measured. In many cases 'mean' est imators and their respective standard errors are calculated afterwards . The determination of drug concentrations in organs as well as in the serum of small animals (mice, rats) in dependence of the time after a dministration often does not permit the establishment of reasonable pr ofiles within one subject suited for conventional pharmacokinetic anal yses and tolerability studies. Frequently, only one experimental value per organ or animal is recorded. The consequence is that most pharmac okinetic parameters are to be estimated on the basis of the mean conce ntrations rather than via the mean of individual parameter estimates. In all cases of a non-linear relationship between a target item and th e concentration, the mean-concentration based estimators and the two-s tage profile based estimators need not coincide. In addition, in the f ormer case variance estimators may be either difficult to obtain or no t deducible. In order to get variance estimators as well as to enable comparisons between different treatment regimens, in addition to bioeq uivalence testing as a step towards human dose finding studies, variou s resampling techniques (parametric and non-parametric bootstrap) were applied to generate pseudo-profiles from independent measurements and compared to their more conventional counterparts where applicable. Si mulation studies based on different predefined pharmacokinetic models (first-order elimination after IV bolus, first-order elimination after first-order absorption, simple capacity-limited kinetics) revealed th at even the non-parametric pseudo-profile stratified 'bootstrap' (resa mpling with replacement per time point) performs quite satisfactorily.