Molnupiravir (Lagevrio) is an antiviral drug that prevents specific RNA viruses from multiplying. It’s utilized to treat COVID-19 in people who have been infected with the SARS-CoV-2 virus.
Molnupiravir is a pro – drug of the synthesized nucleoside derivative N4-hydroxycytidine that works against viruses by causing replicating errors during viral RNA synthesis.
Molnupiravir was created at Emory University by Drug Innovation Ventures at Emory, the university’s drug development firm (DRIVE).
EIDD-1931 was discovered when DRIVE initiated a screening research funded by the Defense Threat Reduction Agency in 2014 to locate an antiviral medication that targets the Venezuelan equine encephalitis virus (VEEV).
The molecule, when converted into the prodrug EIDD-2801 (molnupiravir), demonstrated action against other RNA viruses such as influenza, Ebola, chikungunya, and several coronaviruses.
Medicinal Uses
Molnupiravir is a coronavirus medication utilized for treating mild-to-moderate COVID-19 in adults who have a positive direct SARS-CoV-2 viral test and are at a higher risk of acquiring chronic COVID-19.
When to use
Adult Covid-19 patients with blood oxygen levels of 93 percent and a high-risk illness escalation, including hospitalisation or death, can use it.
The antiviral medication has not been licensed for use in children under the age of 18 or in patients who require immediate hospitalisation.
The tablet is also not allowed to be taken for more than five days in a row.
Dosage
The simple tablet must be taken as soon as possible, preferably within five days after the onset of symptoms. Symptoms include cough, headache, fever, loss of taste or smell, as well as muscle and bodily discomfort.
People with mild to moderate Covid-19 symptoms can take Molnupiravir twice a day for five days at home.
Molnupiravir is administered orally in the form of four 200 mg capsules every 12 hours for a total of 40 capsules over five days.
Dose in kidney patients
In mild to moderate kidney disease (eGFR > 30 ml/min) no dose adjustment
In severe disease (eGFR < 30 ml/min) dose not confirmed.
Contraindications
Pregnancy
Oral administration of molnupiravir to pregnant rats during the organogenesis period resulted in embryo foetal lethality and teratogenicity at 7.5 times the human NHC exposure at the recommended human dose (RHD), at the RHD, foetal development was lowered by 2.9 times the human N-hydroxycytidine (NHC) dose.
At 18 times the human NHC dose at the RHD, oral treatment of molnupiravir to rabbits during organogenesis resulted in lower foetal body weights.
In rats and rabbits, the NOAEL to human NHC exposure safety margin is 0.8 times and 6.5 times, respectively, at the RHD.
Despite the fact that maternal toxicity was seen in both rats and rabbits at all dosage levels where developmental toxicity was observed, a substance-related impact cannot be ruled out.
Molnupiravir is not indicated for use during pregnancy or in women who are not utilising effective contraception.
Breast-feeding
Molnupiravir and the other Lagevrio components are not reported to be detected in human milk, have an effect on human milk secretion, or damage a breastfed infant. There have been no animal lactation studies using molnupiravir.
Breast-feeding should be stopped throughout therapy and for 4 days following the final dosage of Lagevrio due to the risk of molnupiravir causing adverse reactions in a breastfed newborn.
Fertility
There is no human data on the effect of molnupiravir on fertility. Female and male fertility were unaffected in rats exposed to roughly 2 and 6 times the human NHC at the RHD, respectively.
Because it may interfere with bone and cartilage growth, it is not advised for children and teenagers under the age of 18. After repeated administration, bone and cartilage damage was detected in rats.
Adverse effects
The medicine looks to have a clean safety profile, according to the final analysis of Merck’s clinical study, which means there were no major adverse effects among trial volunteers.
Diarrhea (2%), nausea (1%), and dizziness (1%) were all mild or moderate adverse events recorded in the phase III MOVe-OUT research.
Mechanism of action
Molnupiravir works by generating significant mutations in the RNA-directed RNA polymerase that repeats viral RNA, preventing viral replication.
It is converted into -D-N 4-Hydroxy Cytidine 5′-triphosphate (also known as EID-1931 5′-triphosphate or NHC-TP), a ribonucleoside analogue that mimics cytidine.
Instead of using actual cytidine, the virus’s enzyme integrates NHC-TP into newly produced RNA during replication.
Molnupiravir may switch between two kinds (tautomers), one of which is a cytidine (C) mimic and the second a uridine (U) mimic (U).
The virus’s proofreading exonuclease enzymes, which may replace mutant nucleotides with repaired copies, do not detect NHC-TP as a mistake.
When the viral RNA polymerase tries to transcribe molnupiravir-containing RNA, it reads it as C sometimes and U sometimes.
This results in a phenomenon known as viral error catastrophe, or deadly mutagenesis, in which the virus accumulates more alterations in all downstream copies than it can sustain.
Chemistry
Emory University submitted a patent in 2018 that detailed the first molnupiravir synthesis. In the first stage, acetone is utilised as a protective group to make two of uridine’s three hydroxy groups unreactive to isobutyric acid’s acid anhydride, which transforms the third hydroxy group to its ester.
When 1,2,4-triazole and phosphoryl chloride are combined, a reactive intermediate is formed in which the triazole is substituted by hydroxylamine. Finally, the substance is converted to molnupiravir by removing the protective group using formic acid.
Drug interactions
Molnupiravir has not been the subject of any clinical interaction trials. Based on the limited available in-vitro data, there are no significant concerns of clinically meaningful medication interactions while using molnupiravir 800 mg every 12 hours for 5 days.