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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

Authors :
Keisuke Nakamura
Katsukuni Fujimoto
Chihiro Hasegawa
Ikuo Aoki
Hiroyuki Yoshitsugu
Hiroyuki Ugai
Naoyoshi Yatsuzuka
Yoshiyuki Tanaka
Kenichi Furihata
Brian M. Maas
Prachi K. Wickremasingha
Kelly E. Duncan
Marian Iwamoto
Selwyn A. Stoch
Naoto Uemura
Source :
Clinical and Translational Science, Vol 15, Iss 11, Pp 2697-2708 (2022)
Publication Year :
2022
Publisher :
Wiley, 2022.

Abstract

Abstract 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 (Cmax), with a median time to Cmax (Tmax) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC0–inf), area under the concentration versus time curve from zero to 12 h (AUC0–12), and Cmax of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC0–12 and Cmax 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 AUC0–12 and Cmax were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC Cmax with comparable AUC0–inf was seen, supporting administration without regard to food.

Details

Language :
English
ISSN :
17528062 and 17528054
Volume :
15
Issue :
11
Database :
Directory of Open Access Journals
Journal :
Clinical and Translational Science
Publication Type :
Academic Journal
Accession number :
edsdoj.6adea459e92c4204accad4b1f01dc2eb
Document Type :
article
Full Text :
https://doi.org/10.1111/cts.13395