Simulating Oral Absorption with PK-Sim®: Methodology and Application Examples
Willmann, Stefan, Andrea N. Edginton, Walter Schmitt, Marcus Kleine-Besten, and Jennifer B. Dressman
Bayer Technology Services GmbH and Univ. Frankfurt, Germany
PK-Sim(R) is a software tool for physiology-based pharmacokinetic whole-body modelling in laboratory animals (mouse, rat, dog) and humans. It is specifically designed for use in the pharmaceutical research and development environment. Included in this software are modules for the simulation of gastro-intestinal transit, dissolution of solid dosage forms, luminal and gut wall metabolism, absorption from the GI tract, first pass elimination, and enterohepatic circulation. This gastrointestinal module is linked to a whole body distribution model for predicting the resulting plasma and tissue concentration time profiles. Besides a set of physiological input parameters, which are automatically generated by PK-Sim(R), only a few substance specific input parameters are required: lipophilicity, plasma protein binding constant (or alternatively unbound fraction), molweight, pKa values in case of acids or bases, solubility at a given pH, and clearance values.
Application examples will be discussed including a compound demonstrating non-linear exposure due to dissolution limitation, the influence of varying gastric emptying and intestinal transit times on oral absorption profiles of controlled release formulations (cimetidine), and the scaling of oral pharmacokinetics from adults to children (ciprofloxacin).
