Expression Data for PBPK Modeling

​ The most prominent examples of proteins that affect PK are enzymes that catalyze the metabolization of drugs or transporters that can heavily influence drug absorption or distribution. Proteins can also include those which a drug binds to, either by design (drug-target interaction) or as an off- target interaction or side-effect. Such binding can also influence distribution as well as metabolization and excretion of the drug.

​ In physiologically-based PK modeling approaches, it is desirable to mechanistically reflect such relevant drug-protein interactions. In some cases, the addition of one specific protein into the most relevant organ is sufficient to describe a process, e.g. cytochrome P450 3A4-mediated metabolization in the liver. In other cases it may be necessary to consider protein levels in more than one organ. The integration of a protein expression database with PK-Sim makes it easy to assign parameter values for the involved proteins to account for differential protein expression in various organs and assign them to virtual individuals. As such, the user describes the absolute amount of protein in one reference organ and through the use of relative expressions as generated with the protein database, the protein concentrations are fixed for all organs where the protein is present. Details on how to use the protein expression database are described in PK-Sim® - Expression Data. See [46] for an example that demonstrates how taking into account protein expression leads to an increase in PBPK model quality. Alternatively, 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 this in all organs.