Merck & Co., Inc. Rahway, New Jersey, United States
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. The bioequivalence safe-space was to be established for different formulations. Methods: 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 clinically observed results of the Painter et.al 2021 study. Results: Based on PBBM (GastroPlus), the MOV prodrug has a high estimated absorption in human (Fa >85%). Predictive errors were < 25% for Cmax and AUC. 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. Conclusion: The proposed PBBM is suitable for applications to support, along with appropriate MOV dissolution data, potential future formulation changes post-approval. References: Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, Morin MJ, Szewczyk LJ, Painter GR. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2. Antimicrob Agents Chemother. 2021 Mar 1;65(5):e02428-20. doi: 10.1128/AAC.02428-20. Epub ahead of print. PMID: 33649113; PMCID: PMC8092915.
Acknowledgements:The authors are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and may hold equity stock in Merck & Co., Inc., Kenilworth, NJ, USA.
Example of NHC pharmacokinetics (ng/mL) after a 200 mg MOV dose in human. MOV absorption was estimated to be >85% absorption as more than 190 mg MOV reach the systemic circulation (red line). NHC is rapidly generated in vivo as demonstrated by early Tmax (blue line). Observed data are shown in open squares (observed data from Painter et. al 2021.)
.jpg)