Stefan Willmann*, BAYER AG, Bayer Technology Services, Biophysics, Building 470 R. 217, 42096 Wuppertal, Germany,* e-mail: stefan. willmann. sw@ bayertechnology. com. Jörg Lippert, Michael Sevestre, Juri Solodenko, BAYER AG, Bayer Technology Services, Computational Solutions, 51368 Leverkusen, Germany. Franco Fois, Walter Schmitt, BAYER AG, Bayer Technology Services, Biophysics, 40765 Monheim, Germany metabolization processes (given as Michaelis–Menten terms). In particular, the permeation parameters (‘permeability multiplied by surface area’; P× SA), which determine the rate of uptake into an organ, are of major importance in achieving the right partitioning kinetics [1]. Whereas common PBPK solutions neglect this crucial property of drug distribution, PK-Sim® considers the whole process of permeation, backed-up by an experimentally validated set of parameters.

As already mentioned, one fundamental problem in the application of PBPK modeling is the determination of the values of all the model’s parameters [3]. This is particularly true for the organ/plasma partition coefficients, which determine the concentration ratios at steady state, and the above mentioned permeation (P× SA) values. To solve this problem, PK-Sim® contains several proprietary models, which correlate these properties with substancespecific properties that are much easier to determine. In the case of the organ/plasma partition coefficients these properties are lipophilicity [8] and the plasma protein (predominately serum albumin) binding constant, from which the partition coefficients are calculated using a mechanistic formula similar to that described in [3]. The P× SA terms are derived from lipophilicity and molecular weight, based on well known biophysical dependencies, such as Fick’s diffusion law and correlations determined from in-house data. PK-Sim® allows PK simulations in four mammalian species (mouse, rat, dog and human), for which the relevant physiological information have been collected from numerous literature sources.