{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T13:55:39Z","timestamp":1791035739007,"version":"4.1.0"},"reference-count":13,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,4]]},"abstract":"ABSTRACT<\/jats:title>\n \n Molnupiravir, an orally administered drug for the treatment of mild\u2010to\u2010moderate COVID\u201019, is a prodrug of the ribonucleoside \u03b2\u2010D\u2010N4\u2010hydroxycytidine (NHC). NHC incorporation in the SARS\u2010CoV\u20102 RNA strand causes an accumulation of deleterious errors in the genome, resulting in reduced viral infectivity and replication. Exposure\u2010response (E\u2010R) analyses for viral RNA mutation rate and virologic outcomes were conducted using data from three phase 2\/3 studies of molnupiravir (P006, MOVe\u2010IN, and MOVe\u2010OUT). Three dose levels (200, 400, and 800\u2009mg every 12 hours\u00a0[Q12H]) and placebo were evaluated. E\u2010R datasets were generated for SARS\u2010CoV\u20102 RNA mutation and longitudinal SARS\u2010CoV\u20102 RNA viral load. E\u2010R models were defined for RNA mutation rate and viral load change from baseline at days 5 and 10. The models supported plasma NHC AUC\n 0\u201012<\/jats:sub>\n as the appropriate pharmacokinetic driver for assessing E\u2010R relationships. The highest percentage of participants with > 20 low\u2010frequency nucleotide substitutions (LNS) per 10,000 bases, a measure of likely meaningful drug effect, was predicted in the 800\u2009mg Q12H treatment group. A strong drug effect on the reduction of viral load was observed on days 5 and 10. E\u2010R relationships were best represented by an E\n max<\/jats:sub>\n structural model with reasonable consistency in the estimated AUC\n 50<\/jats:sub>\n s (~2.3\u2010fold), across the models, of 10,260 and 4390\u2009nM*hr. for day 5 viral load change from baseline and LNS error rate, respectively. These biomarker E\u2010R curves support the choice of 800\u2009mg Q12H as providing near\u2010maximal drug effect, consistent with findings from the previously published molnupiravir E\u2010R model of clinical outcomes.\n <\/jats:p>","DOI":"10.1111\/cts.70184","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T09:50:31Z","timestamp":1743241831000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comparison of Molnupiravir Exposure\u2010Response Relationships for Virology Response and Mechanism of Action Biomarkers With Clinical Outcomes in Treatment of\n COVID<\/scp>\n \u201019"],"prefix":"10.1111","volume":"18","author":[{"given":"Akshita","family":"Chawla","sequence":"first","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruthie","family":"Birger","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2410-4379","authenticated-orcid":false,"given":"Brian M.","family":"Maas","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youfang","family":"Cao","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wan","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Strizki","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Fridman","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Paschke","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carisa","family":"de Anda","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew L.","family":"Rizk","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Painter","sequence":"additional","affiliation":[{"name":"Ridgeback Biotherapeutics Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne","family":"Holman","sequence":"additional","affiliation":[{"name":"Ridgeback Biotherapeutics Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Sardella","sequence":"additional","affiliation":[{"name":"Simulations Plus Cognigen Corporation Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Painter","sequence":"additional","affiliation":[{"name":"Emory University School of Medicine Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Stone","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02428-20"},{"key":"e_1_2_10_3_1","unstructured":"U. S. Food and Drug Administration.\u201cCoronavirus (COVID\u201019) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID\u201019 in Certain Adults \u201d2021 https:\/\/www.fda.gov\/news\u2010events\/press\u2010announcements\/coronavirus\u2010covid\u201019\u2010update\u2010fda\u2010authorizes\u2010additional\u2010oral\u2010antiviral\u2010treatment\u2010covid\u201019\u2010certain."},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01348-19"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb5883"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkab318"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2895"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40121\u2010023\u201000891\u20101"},{"key":"e_1_2_10_9_1","unstructured":"A.Chawla Y.Cao J.Stone et\u00a0al. \u201cModel\u2010Based Dose Selection for the Phase 3 Evaluation of Molnupiravir (MOV) in the Treatment of COVID\u201019 in Adults \u201d31st Annual European Congress of Clinical Microbiology and Infectious Diseases 2021."},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2100044"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2100043"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2116044"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13031"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13602"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70184","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70184","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70184","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T13:40:44Z","timestamp":1791034844000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,26]]},"references-count":13,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1111\/cts.70184"],"URL":"https:\/\/doi.org\/10.1111\/cts.70184","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,26]]},"assertion":[{"value":"2025-01-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70184"}}