Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland.

We extended a generic whole-body physiologically based pharmacokinetic (PBPK) model for rats and humans for organs of the reproductive and endocrine systems (i.e., the testes and the thyroid gland). An extensive literature search was performed, first, to determine the most generic organ model structures for testes and thyroid across species, and, second, to identify the corresponding anatomic and physiological parameters in rats and humans. The testes and thyroid organ models were implemented in the PBPK modeling software PK-Sim and MoBi. The capability of the PBPK approach to simulate the testes and thyroid tissue concentration data was demonstrated using a series of test compounds. The presented organ model structures and parameterization yielded a close agreement between observed and simulated tissue concentrations over time. The organ models are ready to be used to predict the pharmacokinetics of passively entering drugs in the testes and thyroid tissue in a generic PBPK modeling framework.

Modeling interindividual variability in physiologically based pharmacokinetics and its link to mechanistic covariate modeling.

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.