EXPERIMENTAL-DESIGN AND EFFICIENT PARAMETER-ESTIMATION IN PRECLINICALPHARMACOKINETIC STUDIES

Monte Carlo simulation technique used to evaluate the effect of the ar rangement of concentrations on the efficiency of estimation of populat ion pharmacokinetic parameters in the preclinical setting is described . Although the simulations were restricted to the one compartment mode l with intravenous bolus input, they provide the basis of discussing s ome structural aspects involved in designing a destructive (''quantic' ') preclinical population pharmacokinetic study with a fixed sample si ze as is usually the case in such studies. The efficiency of parameter estimation obtained with sampling strategies based on the three and f our time point designs were evaluated in terms of the percent predicti on error, design number, individual and joint confidence intervals cov erage for parameter estimates approaches, and correlation analysis. Th e data sets contained random terms for both inter- and residual intra- animal variability. The results showed that the typical population par ameter estimates for clearance and volume were efficiently (accurately and precisely) estimated for both designs, while interanimal variabil ity (the only random effect parameter that could be estimated) was ine fficiently (inaccurately and imprecisely) estimated with most sampling schedules of the two designs. The exact location of the third and fou rth time point for the three and four time point designs, respectively , was not critical to the efficiency of overall estimation of all popu lation parameters of the model. However, some individual population ph armacokinetic parameters were sensitive to the location of these times .