Understanding effect site pharmacology of uprifosbuvir, a hepatitis C virus nucleoside inhibitor: Case study of a multidisciplinary modeling approach in drug development

• Published in: CPT: pharmacometrics and systems pharmacology Vol. 10; no. 7; pp. 658 - 670
• Main Authors: van den Berg, Paul, Gao, Wei, Ahsman, Maurice J., Arrington, Leticia, Kesisoglou, Filippos, Miller, Randy, Post, Teun M., Rizk, Matthew L.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-07-2021; John Wiley and Sons Inc; Wiley
• Subjects: Antiviral Agents - pharmacology; Case studies; Cooperative Behavior; Drug development; Drug Development - methods; Drug dosages; Enzymes; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepatitis C; Hepatitis C - drug therapy; Hepatitis C - microbiology; Humans; Hypotheses; Hypothesis testing; Kinetics; Metabolism; Metabolites; Models, Biological; Pharmacodynamics; Pharmacokinetics; Pharmacology; Phosphorylation; Plasma; RNA polymerase; RNA-Dependent RNA Polymerase - antagonists & inhibitors; Tutorial; Tutorials; Uridine - analogs & derivatives; Uridine - pharmacology; Viral Load - drug effects; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 2163-8306; 2163-8306
• DOI: 10.1002/psp4.12644

Uprifosbuvir is a uridine nucleoside monophosphate prodrug inhibitor of the hepatitis C virus 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 pharmacokinetics and pharmacodynamics, a model‐informed drug development (MIDD) framework was initiated at an early stage. Originally scoped as a modeling effort focused on minimal physiologically based pharmacokinetic and covariate analyses, this project turned into a collaborative effort focused on gaining a deeper understanding of the data from drug metabolism, biopharmaceutics, pharmacometrics, and clinical pharmacology perspectives. This article presents an example of the practical execution of a MIDD‐based, cooperative multidisciplinary modeling 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.