molnupiravir

molnupiravir
IUPAC name	(2R,3S,4R,5R)-3,4-dihydroxy-5-[(4-hydroxy-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl)methoxy]oxolan-2-yl]methyl 2-methylpropanoate
Tradename	Lagevrio
Drugs.com	Monograph
MedlinePlus	a622023
Licence US	Molnupiravir
Routes of administration	By mouth
CAS number	2349386-89-4
PubChem	145996610
DrugBank	DB16161
ChemSpiderID	85216912
UNII	YA84KI1VEW
ChEMBL	452365
Chemical formula	C13H19N3O7
Molecular weight	329.31 g·mol−1

molnupiravir is an oral antiviral medication authorized for the treatment of mild-to-moderate COVID-19 in adults at high risk for progression to severe disease. It is a prodrug of the ribonucleoside analog N4-hydroxycytidine, which introduces errors into the viral RNA during replication. Developed through a collaboration between Merck & Co. and Ridgeback Biotherapeutics, its use is typically restricted to settings where other treatments, such as nirmatrelvir/ritonavir, are not accessible or clinically appropriate.

Medical uses

molnupiravir is indicated for the early treatment of COVID-19 in adults with positive results of direct SARS-CoV-2 viral testing, who are within five days of symptom onset and are at high risk for progression to severe COVID-19, including hospitalization or death. This authorization by bodies like the U.S. Food and Drug Administration and the European Medicines Agency is under an Emergency Use Authorization framework. It is not authorized for use as pre-exposure or post-exposure prophylaxis for the prevention of COVID-19, nor for initiation of treatment in patients requiring hospitalization due to COVID-19. The World Health Organization recommends its use only when other antivirals with higher efficacy are unavailable.

Mechanism of action

The drug is metabolized into the active form, N4-hydroxycytidine triphosphate, which mimics the natural ribonucleosides cytidine and uridine. During viral RNA replication by the SARS-CoV-2 RNA-dependent RNA polymerase, this analog is incorporated into the nascent RNA strand. Its ambiguous base-pairing properties cause transitions, introducing errors and leading to an accumulation of mutations in the viral genome, a process known as viral error catastrophe or lethal mutagenesis. This mechanism was initially studied at Emory University and differs from chain-terminating antivirals like remdesivir.

Adverse effects

Common adverse reactions reported in clinical trials include diarrhea, nausea, and dizziness. More serious concerns have been raised regarding potential genotoxicity and embryo-fetal toxicity observed in animal studies, leading to warnings against its use during pregnancy. Regulatory agencies like the U.S. Food and Drug Administration and the Medicines and Healthcare products Regulatory Agency require contraception recommendations for individuals of childbearing potential. Ongoing pharmacovigilance is conducted by organizations including the European Medicines Agency to monitor for any emerging safety signals in treated populations.

Pharmacology

Following oral administration, molnupiravir undergoes rapid hydrolysis to form N4-hydroxycytidine, which is then phosphorylated intracellularly to the active triphosphate form. It achieves broad distribution and the active metabolite has a half-life supporting twice-daily dosing. The drug is primarily eliminated through metabolism, with renal excretion playing a minor role. Its pharmacokinetics were characterized in studies supported by the National Institutes of Health and have shown no clinically significant interactions with major drug-metabolizing enzymes like CYP450.

History and development

The compound originated from research at Emory University's nonprofit drug discovery unit, DRIVE, funded by the U.S. Department of Defense and the National Institute of Allergy and Infectious Diseases. It was initially investigated for Venezuelan equine encephalitis virus before being repurposed for SARS-CoV-2. In 2020, Merck & Co. partnered with Ridgeback Biotherapeutics for further development. The pivotal MOVe-OUT trial results led to its first authorization in the United Kingdom in late 2021, followed by approvals in the United States, Japan, and other nations.

Society and culture

The development and authorization of molnupiravir occurred amidst the global crisis of the COVID-19 pandemic, representing a significant effort to create an oral therapeutic. Merck entered into licensing agreements with the Medicines Patent Pool to facilitate generic production for supply in many low- and middle-income countries. Its role has been debated within the medical community, with some experts from institutions like the University of Oxford citing its lower efficacy compared to alternatives like nirmatrelvir/ritonavir. The drug's code name, MK-4482, and its brand name, Lagevrio, are widely recognized in public health discussions.

Category:Antiviral drugs Category:Hydroxy compounds Category:World Health Organization essential medicines