Is mixed effects modeling or naïve pooled data analysis preferred for the interpretation of single sample per subject toxicokinetic data?
The purpose of this study was to evaluate whether mixed effects modeling (MEM) performs better than either noncompartmental or compartmental naïve pooled data (NPD) analysis for the interpretation of single sample per subject pharmacokinetic (PK) data. Using PK parameters determined during a toxicokinetic study in rats, we simulated data sets that might emerge from similar experiments. Data sets were simulated with varying numbers of animals at each sampling time (4-48) and the number of samples taken (1-3) from each individual. Each data set was replicated 50 times and analyzed using several variations of MEM that differed in the assumptions made regarding intraindividual error, NPD, and a graphical noncompartmental method. These analyses attempted to retrieve the underlying parameter and covariate effect values. We compared these analysis methods with respect to how well the underlying values were retrieved. All analysis methods performed poorly with single sample per subject data but MEM gave less biased estimates under the simulated conditions used here. MEM performance increased when covariate effects were sought in the analysis compared with analyses seeking only PK parameters. Decreasing the number of animals used per sampling time from 48 to 16 did not influence the quality of parameter estimates but further reductions (< 16 animals per sampling time) resulted in a reduced proportion of acceptable estimates. Parameter estimate quality improved and worsened with MEM and NPD, respectively, when additional samples were obtained from each individual. Assumptions made regarding the magnitude of intraindividual error were unimportant with single sample per subject data but influenced parameter estimates if more samples were obtained from each individual. MEM is preferable to both NPD and noncompartmental approaches for the analysis of single sample per subject data but even with MEM estimates of clearance are often biased.
Hing
J P
JP
Department of Anaesthesia, University of Newcastle upon Tyne and Alnwick Research Centre, Sanofi, Alnwick, Northumberland.
Woolfrey
S G
SG
Greenslade
D
D
Wright
P M
PM
D000818:Animals; D003627:Data Interpretation, Statistical; D008954:Models, Biological; D010599:Pharmacokinetics; D051381:Rats; D018401:Sample Size