Influence of Inter-Animal Variability on the Estimation of Population Pharmacokinetic Parameters in Preclinical Studies

Abstract

Single response population (1 sample / animal) simulation studies were carried out (assuming a 1 compartment model) to investigate the influence of inter-animal variability (in clearance (σ_Cl) and volume (σ_v)) on the estimation of population pharmacokinetic parameters. NONMEM was used for parameter estimation. Individual and joint confidence intervals coverage for parameter estimates were computed to reveal the influence of bias and standard error (SE) on interval estimates. The coverage of interval estimates, percent prediction error and correlation analysis were used to judge the efficiency of parameter estimation. The efficiency of estimation of Cl and V was good, on average, irrespective of the values of σ_Cl and σ_v Estimates of σ_Cl and σ_v were biased and imprecise. Small biases and high precision resulted in good confidence intervals coverage for Cl and V. SE was the major determinant of confidence intervals coverage for the random effect parameters, σ_Cl and σ_v and the joint confidence intervals coverage for all parameter estimates. The usual confidence intervals computed may give an erroneous impression of the precision with which the random effect parameters are estimated because of the large standard errors associated with these parameters. Conservative approach to data interpretation is required when biases associated with σ_Cl and σ_v are large.