Uprifosbuvir

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.

Some individuals do not achieve a cure of their hepatitis C virus (HCV) infection due to non-adherence or resistance associated substitutions. Salvage options that are optimised for resistance profiles are essential. We report a 56-year-old Caucasian man with fatigue, depression and confusion in the setting of untreated HCV genotype 3a infection. He received ruzasvir and uprifosbuvir for 12 weeks within a clinical trial. The patient relapsed 4 weeks after the end of treatment and at this time resistance testing showed multiple resistances including a NS5A Y93H mutation. Given that this mutation confers resistance to first line salvage options, sofosbuvir and glecaprevir/pibrentasvir was used for 12 weeks and the patient was cured of HCV infection 12 weeks after the end of treatment. This shows that sofosbuvir and glecaprevir/pibrentasvir is a viable, effective option for second line/salvage therapy of HCV infection in the setting of resistance to NS5A inhibitors with the Y93H mutation.