A Sparse Sampling,Mixed Effects Approach to Toxicokinetic Analyses

Abstract

The use of a satellite group for pharmacokinetic evaluations in preclinical toxicokinetic studies is costly and prohibits direct correlations between toxicological findings and drug concentrations within the same animal. In studies for which some prior information about the kinetics of the drug is available and where the statistical hypotheses to be tested are relatively few, a sparse sampling “population kinetics” approach to the study design has many advantages. This paper describes how the sparse sampling method was used prospectively for a 30-day oral toxicokinetic study involving five rats of each sex and two sampling days. Population means of the kinetic parameters for a two-compartment model were estimated using the NONMEM mixed-effects modeling package, and the posthoc routine used to produce individual Bayesian estimates for each animal. From the individual kinetic parameters, the noncompartmental parameters: AUC, Cmax, and Tmax, were calculated using SAS.