Impact of covariate model building methods on their clinical relevance evaluation in population pharmacokinetic analyses: comparison of the full model, stepwise covariate model (SCM) and SCM+ approaches

Covariate analysis in population pharmacokinetics is key for adjusting doses for patients. The main objective of this work was to compare the adequacy of various modeling approaches on covariate clinical relevance decision-making. The full model, stepwise covariate model (SCM) and SCM+ PsN algorithms were compared in a clinical trial simulation of a 383-patient population pharmacokinetic study mixing rich and sparse designs. A one-compartment model with first-order absorption was used. A base model including a body weight effect on CL/F and V/F and a covariate model including 4 additional covariates-parameters relationships were simulated. As for forest plots, ratios between covariates at a specific value and that of a typical individual were calculated with their 90% confidence interval (CI90) using standard errors. Covariates on CL, V and KA were considered relevant if their CI90 fell completely outside the reference area [0.8–1.2]. All approaches provided unbiased covariate ratio estimates. For covariates with a simulated effect, the 3 approaches correctly identify their clinical relevance. However, significant covariates were missed in up to 15% of cases with SCM/SCM+. For covariate with no simulated effects, the full model mainly identified them as non-relevant or with insufficient information while SCM/SCM+ mainly did not select them. SCM/SCM+ assume that non-selected covariates are non-relevant when it could be due to insufficient information, whereas the full model does not make this assumption and is faster. This study must be extended to other methods and completed by a more complex high-dimensional simulation framework.