Sr Principal Scientist Merck & Co Inc Rahway, New Jersey, United States
Statement of Purpose: Molnupiravir (MOV; MK-4482, EIDD-2801) is an oral antiviral that has received emergency use authorization by the FDA for the treatment of adults with mild-to-moderate COVID-19. MOV is a prodrug of N-hydroxycytidine (NHC; formerly EIDD-1931) which inhibits viral replication of SARS-CoV-2. MOV is classified as a BCS Class I compound (high solubility, high permeability). While MOV showed low permeability with the Caco-2 cell model, the rat intestinal perfusion model showed that MOV has higher permeability than metoprolol. This study is to develop a physiologically based pharmacokinetics modeling to enhance the understanding of drug absorption to inform drug development.
Description of Methods & Materials: To characterize human MOV absorption and systemic pharmacokinetics (PK) of NHC and to assess the bioequivalence of batches from three manufacturing sites, physiologically based biopharmaceutics modeling (PBBM) was undertaken using a dissolution method as per FDA guidance document (Commercial Method).The developed models were qualified against the results the Painter et.al 2021 study.
Data & Results: Based on PBBM with GastroPlus, the MOV prodrug has a high estimated absorption in human (Fa >85%). A NHC PK bioequivalence safe space was established using oral solution and capsule data. Due to the high equilibrium solubility of MOV, and rapid generation of NHC in vivo, minor changes in MOV dissolution do not impact NHC systemic pharmacokinetics.
Interpretation, Conclusion or Significance: The proposed model can be considered for application to support, along with appropriate MOV dissolution data, potential future changes post-approval.
