Expression Data for PBPK Modeling

Proteins play an important role for the PK of many substances. Most prominent examples are enzymes that catalyze the metabolization of drugs or transporters that can heavily influence drug absorption or distribution. Other examples include proteins a drug binds to, either by design (drug-target interaction) or as an off- target or side-effect. Such a binding can also influence distribution as well as metabolization and elimination of the drug.

In physiologically-based modeling approaches it is desirable to mechanistically reflect such relevant drug-protein interactions. While it might sometimes be sufficient to add one specific protein into the most relevant organ and describe the effects it has, e.g. cytochrome P450 3A4 mediated metabolization in the liver, it is in other cases preferable to consider additional organs and proteins. When doing so, it can be challenging to identify or assign parameter values to the involved proteins or processes. In order to assist the expert user in structurally modeling proteins and processes in relevant organs and to reduce the number of involved free parameters to a minimum, we have integrated protein expression databases.

Expert users may query and choose proteins of interest from this database and integrate them into the virtual individuals. Publicly available protein expression differences among organs are already included in this database. The user can choose to only have one parameter to describe the absolute amount of protein in one reference organ and thereby, indirectly, via the included relative expression differences, also fix the absolute amount in all other organs. Similarly, the user can assign one set of kinetic parameters characterizing the drug-protein interaction (e.g. kcat and Km, or kon and koff) and use it in all organs. Details on how to use the protein expression database are described in PK-Sim® - Expression Data. See [46] for an example that demonstrates that taking protein expression into account leads to an increase in PBPK model quality.