Contents

Remdesivir—background and safety

Remdesivir (GS-5734) was originally developed for the potential treatment of Ebola virus infection. However, in clinical trials it was not as effective as other treatments. As remdesivir has antiviral activity against many RNA viruses, it has been repurposed against SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19).

Receive TreatmentUpdate in your inbox:

Remdesivir is a nucleotide analogue and is classed as a “prodrug” by medicinal chemists. Prodrugs do not inherently have antiviral activity. They must enter a cell and be activated by enzymes within that cell. Once the activation process is complete, the activated form of remdesivir tends to remain inside a cell for at least a day.

The viral assembly line

When viruses such as SARS-CoV-2 infect a cell, they hijack the operation of the cell. In effect, viruses turn cells into mini-virus factories, forcing them to churn out copies of SARS-CoV-2. Copies of viruses are assembled in a series of steps analogous to the assembly line in factories. To an infected cell, remdesivir looks like a building block that it would use to make copies of SARS-CoV-2. However, once remdesivir enters and becomes part of the viral assembly line, it causes problems and the cell’s ability to make copies of the virus is compromised.

Entering the body

Remdesivir must be given by intravenous infusion. If remdesivir is taken orally, it is broken down by the liver.

Potential drug interactions

In theory, remdesivir could interact with several enzymes in the liver that break down other medicines. These enzymes include the following:

  • CYP2C8
  • CYP2D6
  • CYP3A4

However, after intravenous infusion, remdesivir rapidly enters cells. Its developer, Gilead Sciences, does not expect it to have significant drug interactions.

The U.S. Food and Drug Administration (FDA) cautions that doctors should not co-prescribe chloroquine or hydroxychloroquine to people who are taking remdesivir, as these other drugs could reduce the antiviral effect of remdesivir. The FDA does not know of actual cases of such an interaction but warns that they could occur.

Another potential drug interaction is between remdesivir and the drug metformin, which is used to help control blood sugar. This potential interaction also needs to be better understood.

Toxicity in animals

Laboratory experiments with cells and animals are a first step to try to explore the potential toxicity of a drug. The results of these experiments can serve as a guide as to what might happen in people with a drug. However, what occurs in animals does not always occur in people.

Remdesivir does not appear to have the potential to cause mutations in cells. However, lab experiments with liver cells suggest that remdesivir can cause temporary liver injury. Further information on the impact of remdesivir on the liver appears below.

Phase I studies

At least four phase I studies (these focus on safety) have been done with 138 healthy human volunteers. In these studies, different doses of remdesivir were administered, ranging from 3 to 225 mg in a single intravenous dose. Multiple doses of 150 mg given intravenously once daily for seven or 14 days were also administered. In some of these people, remdesivir caused a temporary increase in liver enzymes.

—Sean R. Hosein

REFERENCES:

  1. McCreary EK, Pogue JM. Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options. Open Forum Infectious Diseases. 2020;7(4):ofaa105.
  2. Mulangu S, Dodd LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. New England Journal of Medicine. 2019;381(24):2293-2303.
  3. Eastman RT, Roth JS, Brimacombe KR, et al. Remdesivir: A review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Central Science. 2020;6(5):672-683.
  4. Agostini ML, Andres EL, Sims AC, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9(2):e00221-18.
  5. Gordon CJ, Tchesnokov EP, Woolner E, et al. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. Journal of Biological Chemistry. 2020;295(20):6785-6797.
  6. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proceedings of the National Academy of Sciences USA. 2020;117(12):6771-6776.
  7. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nature Communications. 2020;11(1):222.
  8. Davies M, Osborne V, Lane S, et al. Remdesivir in treatment of COVID-19: A systematic benefit-risk assessment. Drug Safety. 2020;43(7):645-656.
  9. Jorgensen SC, Kebriaei R, Dresser LD. Remdesivir: Review of pharmacology, pre-clinical data and emerging clinical experience for COVID-19. Pharmacotherapy. 2020; in press.
  10. Dolin R, Hirsch MS. Remdesivir – An important first step. New England Journal of Medicine. 2020; in press.
  11. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. New England Journal of Medicine. 2020; in press.
  12. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 30;395(10238):1694.
  13. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 – preliminary report. New England Journal of Medicine. 2020; in press.