AbstractA simulation study of the one-compartment open pharmacokinetic model has been made. The population pharmacokinetic parameters which characterize the population of drug residues over time are assumed to be stochastic. A general theoretical model framework for parameter estimation via the method of extended least squares is presented. Formulas approximating the required mean and variance time functions are developed and subsequently used in the simulation study. The effects of four different designs in four different animal populations are presented. The simulated data are those of the single observation per animal per time point type. The characterizing population pharmacokinetic parameters have been analyzed for bias and reliability in both a naive and second-order mean model. Recommendations for choosing an appropriate sampling design are included.