Remdesivir
Remdesivir, sold under the brand name Veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. It is administered via injection into a vein. During the COVID19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID19 in numerous countries.
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 COVID19.
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.
The most common side effect in healthy volunteers is raised blood levels of liver enzymes. The most common side effect in people with COVID19 is nausea. Side effects may include liver inflammation and an infusion-related reaction with nausea, low blood pressure, and sweating.
The US Food and Drug Administration considers it to be a first-in-class medication.
Medical uses
In the European Union, remdesivir is indicated for the treatment of COVID19 in adults and adolescents with pneumonia requiring supplemental oxygen and for adults who do not require supplemental oxygen and who are at increased risk of progressing to severe COVID19.In the United States, remdesivir is indicated for the treatment of COVID19 in people 28 days of age and older and weighing at least who are hospitalized; or not hospitalized and have mild-to-moderate COVID19, and are at high risk for progression to severe COVID19, including hospitalization or death.
In November 2020, the FDA issued an emergency use authorization for the combination of baricitinib with remdesivir, for the treatment of suspected or laboratory confirmed COVID19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.
In Australia, it is approved for those aged four weeks of age and older with a body weight at least with pneumonia requiring supplemental oxygen or those aged four weeks of age and older with body weight at least who do not require supplemental oxygen and who are at high risk of progressing to severe COVID19.
In 2024, a retrospective study found treatment with the antiviral remdesivir plus dexamethasone was associated with fewer deaths in hospitalized COVID-19 patients compared to dexamethasone alone. The combination led to a 26% reduction in mortality at 14 days and a 24% reduction at 28 days.
Side effects
The most common adverse effects in people treated with remdesivir were respiratory failure and blood biomarkers of organ impairment, including low albumin, low potassium, low count of red blood cells, low count of thrombocytes, and elevated bilirubin. Other reported adverse effects include gastrointestinal distress, elevated transaminase levels in the blood, infusion site reactions, and electrocardiogram abnormalities. Remdesivir may cause infusion-related reactions, including low blood pressure, nausea, vomiting, sweating or shivering.Other possible side effects of remdesivir include:
- Infusion-related reactions. Infusion-related reactions have been seen during a remdesivir infusion or around the time remdesivir was given. Signs and symptoms of infusion-related reactions may include: low blood pressure, nausea, vomiting, sweating, and shivering.
- Increases in levels of liver enzymes, seen in abnormal liver blood tests. Increases in levels of liver enzymes have been seen in people who have received remdesivir, which may be a sign of inflammation or damage to cells in the liver.
Pharmacology
Activation
Remdesivir is a protide able to diffuse into cells, where it is converted to GS-441524 monophosphate via the actions of esterases and a phosphoamidase ; this in turn is further phosphorylated to its active metabolite triphosphate by nucleoside-phosphate kinases. This pathway of bioactivation is meant to occur intracellularly, but a substantial amount of remdesivir is prematurely hydrolyzed in plasma, with GS-441524 being the major metabolite in plasma, and the only metabolite remaining two hours after dosing.Mechanism of action
As an adenosine nucleoside triphosphate analog, the active metabolite of remdesivir interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease, causing a decrease in viral RNA production. In some viruses, such as the respiratory syncytial virus, it causes the RNA-dependent RNA polymerases to pause, but its predominant effect is to induce an irreversible chain termination. Unlike with many other chain terminators, this is not mediated by preventing addition of the immediately subsequent nucleotide, but is instead delayed, occurring after five additional bases have been added to the growing RNA chain. For the RNA-dependent RNA polymerases of MERS-CoV, SARS-CoV-1, and SARS-CoV-2, arrest of RNA synthesis occurs after incorporation of three additional nucleotides. Hence, remdesivir is classified as a direct-acting antiviral agent that works as a delayed chain terminator.Pharmacokinetics
In non-human primates, the plasma half-life of the prodrug is 20 minutes, with the main metabolite being the nucleoside, GS-441524. Two hours post injection, the main metabolite GS-441524 is present at micromolar concentrations, whilst intact Remdesivir is no longer detectable. Because of this rapid extracellular conversion to the nucleoside GS-441524, some researchers have questioned whether the active nucleotide triphosphate is truly derived from remdesivir pro-drug removal or whether it occurs by GS-441524 phosphorylation, and whether direct administration of GS-441524 would constitute a cheaper and easier to administer COVID19 drug compared to remdesivir. The activated nucleotide triphosphate form has sustained intracellular levels in PBMC and presumably in other cells as well.Resistance
Mutations in the mouse hepatitis virus RNA replicase that cause partial resistance to remdesivir were identified in 2018. These mutations make the viruses less effective in nature, and the researchers believe they will likely not persist where the drug is not being used.Interactions
Remdesivir is at least partially metabolized by the cytochrome P450 enzymes CYP2C8, CYP2D6, and CYP3A4. Blood plasma concentrations of remdesivir are expected to decrease if it is administered together with cytochrome P450 inducers such as rifampicin, carbamazepine, phenobarbital, phenytoin, primidone, and St John's wort.Using chloroquine or hydroxychloroquine with remdesivir may reduce the antiviral activity of remdesivir. Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir.
Synthesis
Remdesivir can be synthesized in multiple steps from ribose derivatives. The figure to the right is one of the synthesis routes of remdesivir invented by Chun and coauthors from Gilead Sciences.''In vitro'' experiments
An in vitro study of remdesivir assessing antiviral activity against SARS-CoV-2 was performed. Cells were pre-treated with the different doses of remdesivir for 1 hour, and the virus was subsequently added to allow infection for 2 hours. The results found that remdesivir functioned well as an inhibitor of the infection. The study was published as a letter to the editor, and as such did not undergo peer review.Manufacturing
Remdesivir requires "70 raw materials, reagents, and catalysts" to make, and approximately "25 chemical steps." Some of the ingredients are extremely dangerous to humans, especially trimethylsilyl cyanide. The original end-to-end manufacturing process required 9 to 12 months to go from raw materials at contract manufacturers to finished product, but after restarting production in January 2020, Gilead Sciences was able to find ways to reduce the production time to six months.In January 2020, Gilead began working on restarting remdesivir production in glass-lined steel chemical reactors at its manufacturing plant in Edmonton, Alberta. On 2 February 2020, the company flew its entire stock of remdesivir, 100 kilograms in powder form, to its filling plant in La Verne, California, to start filling vials. The Edmonton plant finished its first new batch of remdesivir in April 2020. Around the same time, fresh raw materials began to arrive from contract manufacturers reactivated by Gilead in January.
Another challenge is getting remdesivir into patients despite the drug's "poor predicted solubility and poor stability." In June 2020, Ligand Pharmaceuticals revealed that Gilead has been managing those issues by mixing Ligand's proprietary excipient Captisol with remdesivir at a 30:1 ratio. Since that implies an enormous amount of Captisol is needed to stabilize and deliver remdesivir, Ligand announced that it is trying to boost Captisol annual manufacturing capacity to as much as 500 metric tons.
On 12 May 2020, Gilead announced that it had granted non-exclusive voluntary licenses to five generic drug companies in India and Pakistan to manufacture remdesivir for distribution to 127 countries. The agreements were structured so that the licensees can set their own prices and will not have to pay royalties to Gilead until the WHO declares an end to the COVID19 emergency or another medicine or vaccine is approved for COVID19, whichever comes first. On 23 June 2020, India granted emergency marketing approval of generic remdesivir manufactured by two Gilead licensees, Cipla and Hetero Drugs.