The use of clinical irrelevance criteria in covariate model building with application to dofetilide pharmacokinetic data
Lindbom, L.(1), K. Tunblad(1), L. McFadyen(2), E.N. Jonsson(1), S. Marshall(2), M. O. Karlsson(1)
(1)Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Sweden; 2ECRG, Pfizer Central Research, Sandwich, Kent, United Kingdom
Objectives: To characterise the pharmacokinetics of dofetilide in patients and to identify clinically relevant covariates and their respective contribution to changes in pharmacokinetic parameters. To investigate three different modelling strategies in covariate model building using the analysis of dofetilide as an example: 1) using statistical criteria only or in combination with clinical irrelevance criteria for covariate selection, 2) applying covariate effects on total clearance or separately on non-renal and renal clearances and 3) using separate data sets for covariate selection and parameter estimation.
Methods: Pooled concentration-time data (1445 patients, 10 133 observations) from phase III clinical trials was used. A population pharmacokinetic model was developed using NONMEM. Stepwise covariate model building was applied to identify important covariates using the strategies described above. Inclusion and exclusion of covariates using clinical irrelevance was based on reduction in interindividual variability and changes in parameters at the extremes of the covariate distribution. Parametric separation of the elimination pathways was accomplished using creatinine clearance as an indicator of renal function. The pooled data was split, preserving the relative contribution of each trial, in three parts which were used for covariate selection, parameter estimation and evaluation of predictive performance. Parameter estimations were done using the first-order (FO) and the first-order conditional estimation (FOCE) methods.
Results: A one-compartment model with first order absorption adequately described the data. Using clinical irrelevance criteria rather than only statistical criteria resulted in models containing less parameter-covariate relationships with only a minor loss in predictive power. A larger number of covariates were found significant when the elimination was divided into a renal part and a non-renal part, but no gain in predictive power could be seen with this data set. The FO and FOCE estimation methods gave almost identical final covariate model structures with similar predictive performance.
Conclusion: Clinical irrelevance criteria may be valuable for practical reasons since stricter inclusion/exclusion criteria shortens the run times of the covariate model building procedure and because only the covariates important for the predictive performance are included in the model.