Molnupiravir

Molnupiravir for Outpatient Oral Treatment of Covid-19

New easily distributed oral medications are needed to mitigate the adverse effects of coronavirus disease 2019 (Covid-19). In the recent Covid-19 treatments, multiple drugs have failed in controlling the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, in a recent trial, oral small-molecule antiviral prodrug Molnupiravir has proven to reduce the risk of hospital admissions and deaths from COVID-19 by half.

Mode of Action

Molnupiravir is an oral 400 or 800mg capsule. In the previous studies, one should take a dose every 12 hours. For the 800 mg dose, the active compound (N4-hydroxycytidine) reaches a Cmax of 2970 ng/mL. The Tmax lasts for 1.5hrs and an AUC0-12h of 8360 h*ng/mL. Molnupiravir is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine. This drug forges mutant copies during viral RNA replication, promoting widespread mutations in the replication of viral RNA.

After absorption, Molnupiravir catabolizes to a ribonucleoside analog that resembles cytidine, β-D-N 4-Hydroxy Cytidine 5′-triphosphate. The COVID-19 virus enzyme incorporates NHC-TP into newly replicated ribonucleoside instead of actual cytidine. Molnupiravir can act in two different forms (tautomers). One mimics cytidine (C), and the other resembles uridine (U). COVID-19 virus proofreading exonuclease enzymes fail to recognize NHC-TP as an error, consequently not replacing the mutated nucleotides with corrected versions. As the COVID-19 RNA polymerase tries to replicate, it interprets its RNA as cytidine (C) or sometimes as uridine (U). This failure causes a viral error catastrophe (Lethal mutagenesis), a phenomenon where more mutations copies result than the virus can survive.

Contraindications

Pregnant mothers should avoid using Molnupiravir. Even though there isn’t any data showing the adverse risk of use to the foetus, animal data have shown that this drug could harm the foetus. During the organogenesis of some rats, some studies observed embryofetal lethality and teratogenicity. There was also low fetal weight in rats and rabbits.

A lactating mother should not breastfeed during Molnupiravir treatment to prevent potential adverse reactions in the infant. No available clinical data on the presence of the drug or its metabolites in human breastmilk. There are no known adverse effects on the infant either. There is also no data showing if it affects milk production either.

Molnupiravir can affect bone and cartilage growth in children under 18 years old. Repeated dosing can cause bone and cartilage toxicity, as observed in rats.

Side Effects

There are no known adverse effects following Molnupiravir treatment. However, mild or moderate diarrhea, nausea, and dizziness can occur in the phase III MOVe-OUT of some patients,

There are no known effects of an overdose. The treatment involves outpatient monitoring of any eventuality that might occur.

Molnupiravir does not have any drug interaction. One can take Molnupiravir with or without food. However, when taken with a fatty meal, its bioavailability can be adversely affected up to 35%.

Methods

Participants eligible for this research included outpatients who tested positive for SARS-CoV-2 infection and developed a symptom within one week. These patients were randomized 1:1 to 200 mg Molnupiravir or placebo, or 3:1 to Molnupiravir (400 or 800 mg) or placebo. The administration was carried out two times each day for five days. Nasopharyngeal swabs took specimens for these tests.

Results

Among the patients treated with Molnupiravir, the risk of in-patient treatment or death from COVID-19 was lower by approximately 50%. On Day 3 (p = 0.02), virus isolation was significantly lower in participants receiving 800 mg Molnupiravir (1.9%) versus the placebo group (16.7%). On day 5, the virus was present in participants receiving 400 or 800 mg Molnupiravir, versus 11.1% of those receiving placebo (p = 0.03). Time to viral RNA clearance was low in participants administered 800 mg Molnupiravir versus placebo (p = 0.01). Molnupiravir was generally well tolerated, with similar numbers of adverse events across all groups.

Conclusion

Molnupiravir is the first oral, direct-acting antiviral shown to be highly effective at reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA replication. Molnupiravir has a favorable safety score and tolerability profile across all groups.