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A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19
Molnupiravir (MK‐4482) is an oral prodrug of the antiviral ribonucleoside analog, N‐hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in health...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9538808/ https://www.ncbi.nlm.nih.gov/pubmed/36053806 http://dx.doi.org/10.1111/cts.13395 |
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author | Nakamura, Keisuke Fujimoto, Katsukuni Hasegawa, Chihiro Aoki, Ikuo Yoshitsugu, Hiroyuki Ugai, Hiroyuki Yatsuzuka, Naoyoshi Tanaka, Yoshiyuki Furihata, Kenichi Maas, Brian M. Wickremasingha, Prachi K. Duncan, Kelly E. Iwamoto, Marian Stoch, Selwyn A. Uemura, Naoto |
author_facet | Nakamura, Keisuke Fujimoto, Katsukuni Hasegawa, Chihiro Aoki, Ikuo Yoshitsugu, Hiroyuki Ugai, Hiroyuki Yatsuzuka, Naoyoshi Tanaka, Yoshiyuki Furihata, Kenichi Maas, Brian M. Wickremasingha, Prachi K. Duncan, Kelly E. Iwamoto, Marian Stoch, Selwyn A. Uemura, Naoto |
author_sort | Nakamura, Keisuke |
collection | PubMed |
description | Molnupiravir (MK‐4482) is an oral prodrug of the antiviral ribonucleoside analog, N‐hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well‐tolerated. NHC appeared rapidly in plasma and reached maximum concentration (C (max)), with a median time to C (max) (T (max)) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC(0–inf)), area under the concentration versus time curve from zero to 12 h (AUC(0–12)), and C (max) of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC(0–12) and C (max) were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC‐TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC‐TP AUC(0–12) and C (max) were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC C (max) with comparable AUC(0–inf) was seen, supporting administration without regard to food. |
format | Online Article Text |
id | pubmed-9538808 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95388082022-10-11 A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19 Nakamura, Keisuke Fujimoto, Katsukuni Hasegawa, Chihiro Aoki, Ikuo Yoshitsugu, Hiroyuki Ugai, Hiroyuki Yatsuzuka, Naoyoshi Tanaka, Yoshiyuki Furihata, Kenichi Maas, Brian M. Wickremasingha, Prachi K. Duncan, Kelly E. Iwamoto, Marian Stoch, Selwyn A. Uemura, Naoto Clin Transl Sci Research Molnupiravir (MK‐4482) is an oral prodrug of the antiviral ribonucleoside analog, N‐hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well‐tolerated. NHC appeared rapidly in plasma and reached maximum concentration (C (max)), with a median time to C (max) (T (max)) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC(0–inf)), area under the concentration versus time curve from zero to 12 h (AUC(0–12)), and C (max) of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC(0–12) and C (max) were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC‐TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC‐TP AUC(0–12) and C (max) were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC C (max) with comparable AUC(0–inf) was seen, supporting administration without regard to food. John Wiley and Sons Inc. 2022-09-23 2022-11 /pmc/articles/PMC9538808/ /pubmed/36053806 http://dx.doi.org/10.1111/cts.13395 Text en © 2022 Merck Sharp & Dohme LLC and The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Research Nakamura, Keisuke Fujimoto, Katsukuni Hasegawa, Chihiro Aoki, Ikuo Yoshitsugu, Hiroyuki Ugai, Hiroyuki Yatsuzuka, Naoyoshi Tanaka, Yoshiyuki Furihata, Kenichi Maas, Brian M. Wickremasingha, Prachi K. Duncan, Kelly E. Iwamoto, Marian Stoch, Selwyn A. Uemura, Naoto A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19 |
title | A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19 |
title_full | A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19 |
title_fullStr | A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19 |
title_full_unstemmed | A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19 |
title_short | A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19 |
title_sort | phase i, randomized, placebo‐controlled study of molnupiravir in healthy japanese to support special approval in japan to treat covid‐19 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9538808/ https://www.ncbi.nlm.nih.gov/pubmed/36053806 http://dx.doi.org/10.1111/cts.13395 |
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