Understanding effect site pharmacology of uprifosbuvir, a HCV nucleoside inhibitor: case study of a multidisciplinary modelling approach in drug development.

Uprifosbuvir is a uridine nucleoside monophosphate prodrug inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase. To quantitatively elucidate key metabolic pathways, assess the link between unmeasurable effect site concentrations and viral load reduction, and evaluate the influence of intrinsic and extrinsic factors on PK and PD, a model informed drug development (MIDD) framework was initiated at an early stage. Originally scoped as a modelling effort focused on minimal PBPK and covariate analysis, this project turned into a collaborative effort, focused on gaining a deeper understanding of the data from drug metabolism, biopharmaceutics, pharmacometric and clinical pharmacology perspectives. This paper presents an example of the practical execution of a MIDD-based, cooperative multidisciplinary modelling approach, creating a model that grows along with the team's integrated knowledge. Insights gained from this process could be used in forming optimal collaborations between disciplines in drug development for other investigative compounds.