Integration of dissolution into physiologically-based pharmacokinetic models III: PK-Sim®

Objectives In-silico methods are a cost-effective possibility to support decision making at different stages of the drug development process. Among the various computational methods available, physiologically-based pharmacokinetic (PBPK) modelling represents a well-established tool for mechanistically predicting the pharmacokinetics of drugs and drug candidates. PK-Sim, a component of the Computational Systems Biology Software Suite of Bayer Technology Services GmbH (Leverkusen, Germany) is a commercial PBPK software tool. It is based on a generic model structure for typical animal species from mice to monkey and humans, and allows simultaneous simulation of drug liberation, absorption, distribution, metabolism, and excretion in one model. In this study PK-Sim has been used for the prediction of the in-vivo pharmacokinetics of drugs with a particular focus on the integration of dissolution properties and, due to its leading role in the drug development process, for the performance of different dosage forms administered via the oral route. Methods Three real life case studies have been presented to exemplify the benefits of using PBPK absorption modelling. Key findings In the first example, the in-vivo dissolution rate was directly predicted from the physical properties of different particle formulations using a mechanistic dissolution model of the NoyesWhitney type. In the second case study, the PBPK tool was successfully used to predict the food effect in humans based on data obtained in Beagle dogs. In the third example, the utilization of the software for the support of the development of a combined immediate releasecontrolled release formulation has been described. Conclusions Future perspectives of the use of PBPK modelling have been discussed, with a special focus on the integration of in-vitro dissolution data into PBPK models for oral and non-oral administration of drugs.