title: Pharmacodynamic parameter estimation: population size versus number of samples.
abstract: The purpose of this study was to evaluate the effects of population size, number of samples per individual, and level of interindividual variability (IIV) on the accuracy and precision of pharmacodynamic (PD) parameter estimates. Response data were simulated from concentration input data for an inhibitory sigmoid drug efficacy (E(max)) model using Nonlinear Mixed Effect Modeling, version 5 (NONMEM). Seven designs were investigated using different concentration sampling windows ranging from 0 to 3 EC(50) (EC(50) is the drug concentration at 50% of the E(max)) units. The response data were used to estimate the PD and variability parameters in NONMEM. The accuracy and precision of parameter estimates after 100 replications were assessed using the mean and SD of percent prediction error, respectively. Four samples per individual were sufficient to provide accurate and precise estimate of almost all of the PD and variability parameters, with 100 individuals and IIV of 30%. Reduction of sample size resulted in imprecise estimates of the variability parameters; however, the PD parameter estimates were still precise. At 45% IIV, designs with 5 samples per individual behaved better than those designs with 4 samples per individual. For a moderately variable drug with a high Hill coefficient, sampling from the 0.1 to 1, 1 to 2, 2 to 2.5, and 2.5 to 3 EC(50) window is sufficient to estimate the parameters reliably in a PD study.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ, USA. suzette.girgis@bms.com
authors.forename: Suzette
authors.initials: S
authors.lastname: Girgis
authors.forename: Sudhakar M
authors.initials: SM
authors.lastname: Pai
authors.forename: Ihab G
authors.initials: IG
authors.lastname: Girgis
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Batra
mesh_terms: D006801:Humans; D008962:Models, Theoretical; D010599:Pharmacokinetics; D018401:Sample Size; D013223:Statistics as Topic