Molnupiravir also known as MK-4482/ EIDD-2801 is a new oral antiviral medicine against Covid 19 and its strains. Read more
Molnupiravir also known as MK-4482/ EIDD-2801 is a new investigational oral antiviral medicine that has completed its phase II clinical trials and showed promising results.
Molnupiravir is
developed by Ridgeback Biotherapeutics LP in collaboration with Merck & Co.
It is a potent ribonucleoside analogue that inhibits the replication of
SARS-CoV-2 that is the causative agent of COVID-19. Molnupiravir has shown its
activity during several preclinical models of SARS-CoV-2. It is shown that it
is effective for prophylaxis, treatment, and prevention of transmission of
SARS-CoV-2. The pre-clinical and clinical data of molnupiravir have also shown
that it is effective against the different variants of SARS-CoV-2.
Molnupiravir, previously
known as EIDD-2801, was initially developed by Drug Innovations at Emory
(DRIVE) that is a non-profit biotechnology company completely owned by Emory
University. They introduced it as a broad-spectrum antiviral for the treatment
of equine encephalitis and influenza, but later on, laboratory tests showed that
it is effective against coronaviruses as well. Now Merck is conducting its
phase III clinical trials for COVID-19.
Since the pandemic had
hit several antiviral drugs have been approved and are in queue to be approved,
among that are Remdesivir, oseltamivir, etc. But molnupiravir is one of the
best shots till this time. It is a prodrug of N4-hydroxycytidine (NHC), and a
nucleoside analog that has been investigated for decades now. Molnupiravir
basically stops replication of the copies of the virus’s RNA by causing trouble
to viral RNA-dependent RNA polymerase that is an absolutely critical enzyme for
the replication of any RNA virus. Basically, nucleoside analogs work by pushing
so many errors in the RNA replication step that the end result can't even produce
a competent virus. Further, Molnupiravir has an unusually high barrier to
resistance mechanisms.
The Medicines and
Healthcare products Regulatory Agency (MHRA)’s makes the UK the first country
in the world who approve Molnupiravir for the treatment of COVID-19. It is
branded as Lagevrio in the UK and has been in the global spotlight for the
treatment of Covid-19, as it showed promising results so far. It is the world’s
first approved antiviral drug for the treatment of COVID-19 that can be taken
by mouth rather than administered intravenously. It means it can be
administered outside of a hospital setting, before the progression of Covid-19
to a severe stage. Clinical trials showed that molnupiravir show promising
results only when administered at the early stages of infection. The MHRA has
recommended that individuals should start treatment with molnupiravir as soon
as they came to know that they are COVID-19 positive i.e., within the five days
of the onset of symptoms.
Molnupiavir was
introduced in the early 2000s as preventative medicine and treatment against
SARS-CoV, MERS, or other respiratory viruses. It is effective against many
viruses that employ an RNA-dependent RNA polymerase, SARS-CoV-2 virus is also
from the same class. The polymerase is an enzyme that copies the genetic
material of the virus into new genetic material and produces the messenger RNAs
that direct the production of all the viral proteins. Molnupiravir is a
shape-shifter that is why it is called a tautomer. It has two forms, one which
closely resembles uracil and the other cytosine. And, because of these two
different forms, the replicating polymerase develops transition mutations, when
it is recopied and causes the conversion of U nucleotide to C nucleotide and C
nucleotide to U nucleotide. This newly copied RNA contains Molnupiravir that
causes fatal flaws in the sequence and replication stops. This results in the
shortening of infection and limiting the transmission.
In vitro studies revealed
that Molnupiravir showed a dose-dependent drop in the production of viruses
such as SARS-CoV-2. This is because the RdRp of SARS-CoV-2 and SARS-CoV, which
the drug was initially intended to treat, have 99.1% nucleotide similarity.
Whole-genome deep-sequencing showed dose-dependent accumulation of random
low-frequency mutations. The effectiveness of the drug was rapid and intact
upon repeat exposure of virus populations to the drug, which confirms that none
of the random mutations’ mediate resistance to the drug.
The results of clinical
trials released by Merck & Co. showed that Molnupiravir in its full dosage
causes a reduction in days to negativity for the virus in nasopharyngeal swabs
taken from participants with symptomatic SARS-CoV-2 infections. Five days after
the dose administration of Molnupiravir, 0% of patients were positive for the
coronavirus (0/47) as compared to 24% of the patients of the placebo group
(6/25). Although the details and study size are limited a measurable drop in
infection length is significant in patients taking Molnupiravir. The studies
also revealed that Molnupiravir not only prevents the worsening of the
infection but also prevents the transmission of the disease.
In addition to the
reduction of transmission of Covid-19, Molnupiravir is also useful against
influenza, ebola, and a large swath of other viruses. Its development seems to
be a major advancement in virus control as it is not only effective against
Covid-19 and its variants but also variants of other viruses.
The COVID-19 (SARS-CoV-2)
pandemic continues to scar the world, despite the vaccination. But the
emergence of new variants of COVID-19 is alarming. Many experts have said that
the elimination of COVID-19 is an unrealistic goal and this pandemic could be
endemic. There is a need for the development of treatment for vaccine-resistant
variants.
In this scenario, where
the extraordinary impact of this pandemic demands a safe, effective, and
affordable antiviral drug for the prevention & treatment of COVID-19, that
also limits the spread of the virus would be an invaluable tool. In such
circumstances, Merck’s investigational oral drug molnupiravir reduces the risk
of hospitalization by 50% in patients with COVID-19, has generated enthusiasm,
and is claimed as a “breakthrough drug” and a “game-changer drug”.
As the name
“Molnupiravir” (the name is a reference to Thor’s hammer, Mjölnir) suggests it
could be a powerful drug. The advantage of molnupiravir is that it can be taken
to the home and there is no need to get hospitalized. There is a hope that it
may be useful for people with weak immune systems, and for people who may not
get benefit from vaccination.
Treatments for Covid-19
are a vital component of the response to the pandemic. Although new drugs like
molnupiravir require more testing and review, it is believed that Molnupiravir will offer a strong and targeted treatment for COVID-19. A drug
like molnupiravir could be especially useful because it is administered in the
early stages of the disease. Since it’s just a pill, it may spare the patient
from visiting a clinic or a hospital setting for the transfusion of treatments
like monoclonal antibodies. That reduces the chances of an infected patient
transmitting the virus to the medical staff, and it averts potential
complications associated with transfusions. Also, pills are also much easier to
store and transport as compared to transfused drugs and vaccines, so they can
reach more remote areas with fewer resources. Merck said that they are setting
up tiered pricing for molnupiravir, meaning that it could cost less in other
countries.
There is a gap due to the shortage of vaccines and also the development of new variants of COVID-19 (SARS-CoV)
that are resistant to vaccines as Omicron. Also, there are many countries that do not get
even a single shot of vaccine because of transportation issues and conditions
for storage. There is hope that this oral antiviral drug, Molnupiravir will
fill that gap and would be an effective medicine in controlling this pandemic
of COVID-19. As it is proved to be an effective remedy for coronavirus.
The most obvious downside
to any drug is the safety risks i.e., unexpected side effects. Such effects
arise when a drug affects the other parts of the body in addition to those that
it should. Molnupiravir is designed such that it hits the virus only but does
not affect the bodies of the people who are taking the drug. It is, therefore,
claimed to be a safe drug. But until any conclusive evidence arrives, it is
hard to say that molnupiravir will be absolutely safe.
Since molnupiravir causes
mutation in the genetic makeup of novel coronavirus that raises a question
that: can molnupiravir induce mutational errors in DNA as well? In this regard,
Merck carried out specific tests in animals to examine the drug’s potential to
cause DNA mutations. Merck announced on April 15 that the totality of its data
indicated that molnupiravir is neither mutagenic nor genotoxic.
ABOUT MOLNUPIRAVIR
SUMMARY
OF PRODUCT CHARACTERISTICS
Therapeutic
Indication
Molnupiravir
is indicated for the treatment of mild to moderate COVID-19 in adults who are
SARS-COV-2 positive and have at least one risk factor that their disease can
worsen and they get hospitalized. Molnupiravir reduces the risk of
hospitalization by 50%.
Posology and method of
administration
Posology
Adults
The
recommended adult dose of Molnupiravir is 800 mg that is four capsules of 200mg
taken orally twice a day (every 12 hours) continuously for 5 days.
The
safety and efficacy of molnupiravir for periods longer than 5 days have not
been established yet.
It
needs to be noted that Molnupiravir should be administered as soon as you are
diagnosed with coronavirus (COVID-19), within 5 days of onset of symptoms.
Missed
dose
The
patient doesn’t have to miss the dose of Molnupiravir as it is needed to take
it twice a day, continuously for 5 days. You can put an alarm or reminder to
take the dose. But if you forget to take your dose, you can take it immediately
as soon as you remember within 10 hours. But if you remember after 10 hours
then do not the missed dose, but take your regular next dose at its right time.
Do not take the double dose to make up for the missed dose.
Special
populations
Elderly
No
dose adjustment is required for Molnupiravir based on age.
Renal
impairment
No
dose adjustment is required for patients with renal impairment.
Hepatic
impairment
No
dose adjustment is required for patients with hepatic impairment.
Pediatric
population
The
safety and efficacy of Molnupiravir for patients less than 18 years of age have
not been established yet. As no clinical data is available for this age group.
Method
of administration
Molnupiravir
is for oral use only.
Molnupiravir
can be taken with or without food.
It
is necessary to swallow the whole capsule with a sufficient amount of fluid
(e.g., a glass of water). Do not crush, chew, or open the contents of capsules.
Contraindications
Hypersensitivity
to the active substance or any of the excipients.
Special warnings and
precautions for use
Sodium
Molnupiravir
caspule contains less than 1 mmol sodium (23 mg) per dose of 4 capsules. It can
be stated that essentially this medicine is 'sodium-free.
Interaction with other
medicinal products and other forms of interaction
This
medicine is under clinical trials and only limited data is available for drug
interactions. So far, no drug interactions have been identified based on the
available data. No clinical interaction studies have been performed with
molnupiravir.
Molnupiravir is hydrolyzed inside the body to n-hydroxycytidine (NHC) before reaching the systemic circulation. Uptake of NHC and metabolism to NHC-TP are mediated by the same pathways involved in endogenous pyrimidine metabolism. NHC is not a substrate of major drug-metabolizing enzymes or transporters. Based on in vitro studies, neither molnupiravir nor NHC is an inhibitor or inducers of major drug-metabolizing enzymes or inhibitors of major drug transporters. Therefore, the potential for molnupiravir or NHC to interact with concomitant medications is considered unlikely.
Fertility, pregnancy, and
lactation
Pregnancy
There
are no data available related to the use of Molnupiravir in pregnant women.
However, animal studies have shown reproductive toxicity.
Molnupiravir
is not recommended to use during pregnancy. Women of childbearing potential
should use effective contraceptives during the treatment with Molnupiravir and
continue to use contraceptives for 4 days after the last dose of Molnupiravir.
Breast-feeding
It
is unknown whether molnupiravir or any of the components of molnupiravir are
present in human milk, affect human milk production, or affect the breastfed
infant. Animal lactation studies with molnupiravir have not been conducted.
Based
on the potential for adverse reactions on the infant from Molnupiravir,
breastfeeding is not recommended during treatment and for 4 days after the last
dose of Molnupiravir.
Fertility
There
were no effects observed on female or male fertility in rats with the use of
Molnupiravir. However, the effect on human fertility male/female has not been
studied yet.
Effects on ability to
drive and use machines
No
data is available on the effects of molnupiravir, on the ability to drive and
use machines.
Undesirable effects
Summary
of the safety profile
In
an interim analysis of Phase III clinical trials of subjects with mild to
moderate COVID-19 treated with molnupiravir (n=386), the most common adverse
reactions (≥1% of subjects) reported during treatment and during 14 days after
the last dose were diarrhea (3%), nausea (2%), dizziness (1%) and headache (1%)
all of which were Grade 1 (mild) or Grade 2 (moderate).
Tabulated
list of adverse reactions
The adverse reactions listed below are according to the system organ class and frequency. Frequencies are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000).
Tabulated list of adverse
reactions
|
Frequency |
Adverse
Reaction |
|
Nervous
system disorders |
|
|
Common |
dizziness,
headache |
|
Gastrointestinal
disorders |
|
|
Common |
diarrhea,
nausea |
|
Uncommon |
vomiting |
|
Skin
and subcutaneous tissue disorders |
|
|
Uncommon |
rash,
urticaria |
Reporting of
suspected adverse reactions
Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows a continous monitoring of the benefit / risk of the medicinal product. Healthcare professionals (doctor, nurse, pharmacist) are asked to report any suspected adverse reactions reported by their patients.
Overdose
There is no human
experience of overdosage with Molnupiravir as the medicine is given under
supervision of professionals to conduct clinical trials. Treatment of overdose
with Molnupiravir should consist of general supportive measures including the
monitoring of the clinical status of the patient. Haemodialysis is not expected
to result in effective elimination of NHC.
Pharmacological
properties
Pharmacodynamic
properties
Pharmacotherapeutic
group: Antivirals for systemic use, direct acting antivirals
ATC
code: not yet assigned.
Mechanism
of action
Molnupiravir is a prodrug
and is metabolised to N-hydroxycytidine (NHC) that is a ribonucleoside analogue.
NHC distributes into cells where it is phosphorylated to form the
pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP acts by a
mechanism known as viral error catastrophe. NHC-TP incorporation into viral RNA
by the viral RNA polymerase, results in an accumulation of errors in the viral
genome leading to inhibition of replication.
Antiviral Activity
NHC was active in cell
culture assays against SARS-CoV-2 with 50% effective concentrations (EC50)
ranging between 0.67 to 2.66 µM in A-549 cells and 0.32 to 2.03 µM in Vero E6
cells. NHC had similar activity against SARS-CoV-2 variants B.1.1.7 (Alpha),
B.1351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) with EC50 values of 1.59,
1.77 and 1.32 and 1.68 µM, respectively. No impact was observed on the in
vitro antiviral activity of NHC against SARS-CoV-2 when NHC was tested
in combination with abacavir, emtricitabine, hydroxychloroquine, lamivudine,
nelfinavir, remdesivir, ribavirin, sofosbuvir, or tenofovir.
Pharmacodynamic effects
The relationship between
NHC and intracellular NHC-TP with antiviral efficacy has not been clinically
evaluated yet.
Resistance
No amino acid
substitutions have been identified in SARS-CoV-2 that is associated with
resistance to NHC in Phase 2 clinical trials of molnupiravir evaluation, for
the treatment of COVID-19. However, studies to evaluate selection of resistance
to NHC with SARS-CoV-2 in cell culture have not been completed.
Clinical efficacy and
safety
Clinical data are based
on an interim analysis of data from 775 randomized subjects in the Phase 3
MOVe-OUT trial. MOVe-OUT was a randomized, placebo-controlled, double-blind
clinical trial studying molnupiravir for the treatment of non-hospitalized
patients with mild to moderate COVID-19 who were at risk for progressing to
severe COVID-19 and/or hospitalization. Eligible subjects were 18 years
of age and older and had one or more pre-defined risk factors for disease
progression: 60 years of age or older, diabetes, obesity (BMI >30), chronic
kidney disease, serious heart conditions, chronic obstructive pulmonary
disease, or active cancer. The study included symptomatic subjects not
vaccinated against SARS-CoV-2 and who had laboratory confirmed SARS-CoV-2
infection and symptom onset within 5 days of enrolment. Subjects were randomized
1:1 to receive 800 mg of Molnupiravir or placebo orally twice daily for 5 days.
At baseline, in all randomized
subjects, the median age was 44 years (range: 18 to 88 years); 14% of subjects
were 60 years of age or older and 3% were over 75 years of age; 52% of subjects
were male; 52% were White, 6% Black or African American, 2% Asian; 58% were
Hispanic or Latino. Forty-nine percent of subjects received Molnupiravir or
placebo within 3 days of COVID-19 symptom onset. The most common risk factors
were obesity (77%), 60 years of age or older (14%), and diabetes (14%).
Overall, baseline demographic and disease characteristics were well balanced
between the treatment arms.
Below table provides the results of the primary endpoint (the percentage of subjects who were hospitalized or died through Day 29 due to any cause). Treatment with Molnupiravir resulted in a 6.8 percentage point reduction in the risk of hospitalization or death (approximately 50% relative risk reduction). All 8 subjects who died through Day 29 were in the placebo group and were hospitalized prior to their death.
Pharmacokinetic
properties
Molnupiravir is a
5´-isobutyrate prodrug that is hydrolyzed to NHC before entering the systemic
circulation. The pharmacokinetics of NHC are similar in healthy subjects as
well as in patients with COVID-19.
The pharmacokinetics of
NHC at steady-state following administration of 800 mg molnupiravir every 12
hours are provided in below table.
Pharmacokinetics of NHC
after administration of 800mg Molnupiravir every 12 hours
|
NHC Geometric Mean
(%CV) |
||
|
AUC0-12hr (ng×hr/mL)* |
Cmax (ng/mL)
† |
C12hr (ng/mL)* |
|
8260 (41.0) |
2970 (16.8) |
31.1 (124) |
|
%CV: Geometric
coefficient of variation. * Values were obtained
from population PK analysis. †Values were obtained
from a Phase 1 study of healthy subjects. |
||
Absorption
Following twice-daily
oral administration of 800 mg molnupiravir, the median time to peak plasma NHC
concentrations (Tmax) was 1.5 hours.
Effect of Food on Oral
Absorption
In healthy subjects, the administration of a single 200 mg dose of molnupiravir with a high-fat meal resulted in a 35% reduction in NHC peak concentrations (Cmax), However, the area under the curve (AUC) was not significantly affected.
Distribution
It is found that NHC does
not bind to plasma proteins.
Elimination
The effective half-life
of NHC is approximately 3.3 hours and the fraction of dose excreted of NHC in
the urine was ≤3% in healthy participants.
Other special populations
Gender, Race, Age
Population
pharmacokinetic analysis showed that age, gender, race, and ethnicity do not
affect the pharmacokinetics of molnupiravir / NHC.
Pediatric Patients
The pharmacokinetics of
molnupiravir has not been studied in pediatric patients.
Renal Impairment
As NHC is not meant for renal clearance. Therefore, no dose adjustment is required in patients with any degree of renal impairment. In a population PK analysis, mild or moderate renal impairment did not have a meaningful impact on the pharmacokinetics of molnupiravir / NHC. The pharmacokinetics of molnupiravir and NHC have not been evaluated in patients with eGFR less than 30 mL/min or on dialysis.
Hepatic Impairment
The pharmacokinetics of molnupiravir / NHC has not been evaluated in patients with hepatic impairment. Preclinical data indicate that hepatic elimination is not expected to be a major route of NHC elimination therefore hepatic impairment is unlikely to affect NHC exposure. So, no dose adjustment is required in patients with hepatic impairment.
Reference Links
| Specifications | Descriptions |
|---|---|
| Product Type: | Tablets |
