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How Remdesivir Works in COVID-19

How Remdesivir Works in COVID-19

Nabin Bista by Nabin Bista
May 2, 2021
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How Remdesivir Works in COVID-19
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How Remdesivir Works in COVID-19

How Remdesivir Works in COVID-19

Remdesivir is a broad-spectrum antiviral medication It is administered via injection into a vein. During the COVID-19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID‑19 in around 50 countries. Updated guidelines from the World Health Organization in November 2020 include a conditional recommendation against the use of remdesivir for the treatment of COVID-19.

On October 22, 2020, FDA approved Remdesivir for use in adults and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of COVID-19 requiring hospitalization. Remdesivir should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care.

Remdesivir was originally developed to treat hepatitis C, and was subsequently investigated for Ebola virus disease and Marburg virus infections before being studied as a post-infection treatment for COVID-19.

The most common side effect in healthy volunteers is raised blood levels of liver enzymes (a sign of liver problems). The most common side effect in people with COVID‑19 is nausea. Side effects may include liver inflammation and an infusion-related reaction with nausea, low blood pressure, and sweating.

Remdesivir is a prodrug that is intended to allow intracellular delivery of GS-441524 monophosphate and subsequent biotransformation into GS-441524 triphosphate, a ribonucleotide analogue inhibitor of viral RNA polymerase.

How Remdesivir Works in COVID-19/Mechanism of Action Remdesivir 

In SARS-CoV and MERS-CoV, remdesivir-TP interferes with the nsp12 polymerase, which is a multisubunit RNA synthesis complex of viral nonstructural proteins (nsp’s) produced as cleavage products of viral polyproteins. As nsp12 is highly conserved across the coronavirus family, it is most likely that the mechanism of action (MOA) of remdesivir does not differ significantly among CoVs . Like in EBOV, remdesivir-TP efficiently inhibits the replication of SARS-CoV and MERS-CoV by causing delayed chain termination when being incorporated into the replicating RNA. A recent biochemical analysis revealed that in SARS-CoV-2, remdesivir-TP causes the termination of RNA synthesis at three positions after the position where it is incorporated (i + 3). This mechanism was nearly identical in RdRps of SARS-CoV and MERS-CoV . The premature termination of RNA synthesis ultimately abrogates further transcriptional and translational processes needed for the generation of new virions. The resulting antiviral effects of remdesivir have been studied in different cell-based models.

 

How Remdesivir Work in COVID 19
Intracellular activation of remdesivir (GS-5734) and inhibition of coronavirus replication. Passage through the cell membrane by remdesivir is facilitated by the prodrug component attached to the nucleoside core. Upon entering the target cell, the pronucleotide undergoes further phosphorylation steps to become the active triphosphate metabolite that effectively inhibits viral RNA replication. Delayed chain termination is caused by the following processes: (i) misintegration of nucleoside triphosphate (NTP) into replicating RNA by RdRp, (ii) prevention of further chain elongation after NTP plus 3 additional nucleosides, and (iii) premature termination of RNA synthesis.

Mechanism of Action Remdesivir

Inhibits SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication

Adenosine nucleotide prodrug that distributes into cells, where it is metabolized to form the pharmacologically active nucleoside triphosphate metabolite

Metabolism of remdesivir to remdesivir triphosphate (RDV-TP) demonstrated in multiple cell types

RDV-TP acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA

Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases with low potential for mitochondrial toxicity


Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 100mg/vial

injection, concentrated solution

  • 100mg/20mL (5mg/mL)
Coronavirus Disease (COVID-19)

Indicated for adults and pediatric patients aged ≥12 years who weigh ≥40 kg for treatment of COVID-19 requiring hospitalization

Day 1 loading dose: 200 mg IV infused over 30-120 min, THEN

Day 2 and thereafter: 100 mg IV qDay

Side Effect of Remdesivir 

The most common adverse effects in people treated with remdesivir were

  • eGFR decreased(18%)
  • Decreased CrCl (calculated by Cockcroft-Gault) (10-18%)
  • Creatinine increased (5-15%)
  • Hemoglobin decreased (6-15%)
  • Glucose increased (11-12%)
  • Lymphocytes decreased (11%)
  • Prothrombin time increased (9%)
  • ALT increased (3-8%)
  • AST increased (6-7%)
  • Nausea (3-5%)
  • Bilirubin increased (2%)
  • Hypersensitivity reactions (<2%)
  • Generalized seizure (<2%)
  • Rash (<2%)


Reference: 

  • Remdesivir against COVID-19 and Other Viral Diseases

  • https://reference.medscape.com/drug/veklury-remdesivir-4000090#10


  • Why You Should Not Use Ivermectin to Treat or Prevent COVID-19
  • DDA has given Emergency use Authorization of  Vero Cell vaccine in Nepal

 

 

 

 

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Nabin Bista

Nabin Bista

Hello, Thank You for visiting my blog I am Nabin Bista, Dedicated and self motivated young Registered Pharmacist from Nepal. Blogging is my passion. I did my B Pharmacy from Institute of Medicine - IOM, Currently working as Hospital Pharmacist at Patan Academy of Health Sciences (PAHS). If you want me to write about any posts that you found confusing/difficult, please mention in the comments below.

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