An Application of the Population Approach to Animal Pharmacokinetics During Drug Development

Abstract

Serum concentrations of a drug under development were obtained from an animal pharmacokinetic study using the one sample per animal design, and analyzed using the population data analysis program, NONMEM. A two compartment open model with IV administration was fitted to the data. Although sex and weight were not predictors of clearance (CL), sex helped to explain the variability in the volume of central compartment (V₁). the variability in CL and V₁ were 23.5 and 23.2%, respectively, while the variability in the transfer rate constants, k₁₂ and k₂₁ were infinitesimal. Removal of variability in these micro rate constants did not affect the NONMEM objective function. the inter-animal variability estimated in these parameters were actually a composite of inter-animal variability and residual intra-animal variability since there was no information in the data sets for the estimation of the latter. the typical population parameter values with relative standard errors (expressed as percent coefficient of variation) are: CL (ml/min) of 0.4 (7.8%), V_{1 male} (ml) of 19.1 (6.7%), and V_{1 female} (ml) of V_{1 male}* 0.8 (10.4%), k₁₂ (h⁻¹) of 0.01 (15.3%), and k₂₁ (h⁻¹) of 0.005 (38.5%). Although NONMEM permitted some explanation of variability (in a group of animals (rats) used in this quantic pharmacokinetic study) in terms of sex, efficient partitioning between inter-and residual intra-animal variability would require an increase in the number of samples per animal.