PK-Sim® Express – Direct integration of gene expression data into PBPK models with PK-Sim®

Computational Systems Biology experts at Bayer Technology Services have developed a new concept for directly integrating tissue specific expression data into physiologically-based pharmacokinetic (PBPK) models.

The main principle of physiologically-based pharmacokinetic (PBPK) modeling is to integrate as much physiological information as possible to explain and predict pharmacokinetics of drugs. In order to obtain a more detailed mechanistic description of metabolic and active transport processes dependent on the availability of specific proteins (i.e. enzymes and transporters) in different tissues, a novel method integrating expression data as a surrogate for protein abundance into PBPK models was developed at Bayer Technology Services. The resulting model presents a more accurate physiological description of the molecular mechanisms underlying metabolism and distribution and additionally contains a lower number of free parameters. For this approach, our modeling experts have developed a new database based on relative tissue specific expression data from different publicly available sources: EST sequences from UNIGENE, whole genome expression arrays from ArrayExpress and RT-PCR derived gene expression estimates from literature. The new modeling concept was evaluated by building a PBPK model for pravastatin as a test case, considering pravastatin uptake by OATP1B1 in the liver, transport by MRP2 in intestine, liver and kidney, and metabolization by sulfotransferases (SULTs) in intestine, liver and kidney. Using relative expression data resulted in a successful description of pravastatin pharmacokinetics, clearly showing the benefit of this method for building PBPK models. Moreover, this new approach combines top-down pharmacokinetic modeling at the organism level with bottom-up measurements at the cellular scale, thus enabling comprehensive insights from a truly systemic perspective relevant e.g. for clinical studies. The new database PK-Sim Express is thought to greatly simplify multiscale pharmacokinetic modeling and is envisioned to incorporate additional kinds of “omics” data in the future. The integration into our software platform is underway and the new feature will be available in 2011.