Covariate modeling is a key step in the analysis of clinical data and is essential for establishing dosing recommendations for specific populations, e.g., in obese individuals and children. So far, no systematic approach exists to leverage the knowledge inherent in physiologically based pharmacokinetic (PBPK) models in this context. We introduce (i) a novel approach to model interindividual variability in PBPK models based on lean body weight (LBW); and (ii) a systematic approach to translate interindividual variability into the design of mechanistic covariate models. We derive a new covariate relation for the volume of distribution at steady state (Vss) that seamlessly integrates body weight and LBW as covariates, with a weighting factor depending on the physicochemical properties of the drug. We further show that for children, PBPK-based extrapolation and allometric scaling result in very similar predictions for Vss and blood clearance.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e4; doi:10.1038/psp.2012.3; advance online publication 26 September 2012.