Remdesivir

DRUG CLASS

Phosphoramidate pro-drug of an adenosine analogue

PHARMACEUTICS

• 100mg powder for reconstitution in 0.9% NaCl or 5% glucose, or
• 100 mg/20 mL solution (5mg/mL)

DOSE

• 200 mg IV loading dose followed by 100 mg IV daily for 5 days
• Infused over 30-120 minutes

MECHANISM OF ACTION

Nucleotide analogue causes delayed RNA chain termination impairing viral replication

• Inside cells, remdesivir is converted to the GS-441524 monophosphate, which undergoes rapid conversion to the pharmacologically active nucleoside triphosphate form GS-443902
• nucleoside triphosphate GS-443902 is incorporated into nascent RNA chains by viral RNA-dependent RNA polymerase, causing delayed RNA chain termination and inhibiting viral replication

Mammalian RNA-dependent RNA polymerase has much higher selectivity for ATP than the viral enzyme, so replication is not significantly inhibited.

INDICATIONS

COVID19

• Moderate severity disease requiring supplemental oxygen therapy to keep SpO2 >92%

Potential role in treatment of other RNA viruses, such as:

• Coronaviruses (e.g. MERS)
• Filoviruses (e.g. Ebola)

CONTRA-INDICATIONS

• Severe/ critical COVID19 disease requiring
  • mechanical ventilation (course can be completed if initiated appropriately prior to ventilation)
  • ECMO  (course can be completed if initiated appropriately prior to ECMO)

• Abnormal LFTs (ALT >5x upper limit of normal (ULN) and bilirubin >2 x ULN)
• Hypersensitivity
• Renal failure (eGFR <30 mL/min or receiving renal replacement therapy)
• Multi-organ failure

PHARMACOKINETICS

From Deb et al (2021) and Pubchem:

• A: poor oral availability with high first pass metabolism; slow variable release when given IM; potential for use via inhalational route
• D: widely distributed but does not cross blood-brain barrier; 90% protein-binding; VD ~1L/kg. Intracellular t1/2 of the triphosphate is 14 h to 24 h, allowing once daily dosing.
• M: prodrug is metabolized intra-cellularly through hydrolysis (especially carboxylesterase 1 (CES1) via an alanine metabolite (GS-704277) to its triphosphate active form (GS-443902); hepatic clearance is dependent on hepatic blood flow (high extraction ratio); also partially metabolized by CYP2C8, CYP2D6, and CYP3A4.
• E: predominantly renal (75%) and biliary excretion. excreted mostly as GS-441524 (monophosphate) with plasma t1/2 = 27 h; remdesivir and GS-704277 (alanine metabolite) both have plasma t1/2 ~1-2h.

DRUG-DRUG INTERACTIONS (DDI)

• Chloroquine and hydroxychloroquine (antagonise activation of remdesivir and antiviral activity)
• Possible interactions with drugs that affect tissue and plasma esterase (e.g. dexamethasone induction of CES1) or cytochrome enzymes (CYP2C8, CYP2D6, and CYP3A4).
• P-glycoprotein can efflux remdesivir out of the cellular compartment potentially leading to lower intracellular levels and effectiveness.
• See table 2 of Deb et al (2021) for important potential interactions.

PREGNANCY/ LACTATION

• Uncertain

ADVERSE EFFECTS

The adverse effect profile of remdesivir is still emerging (Fan et al, 2020)

• Bradycardia (reversible with cessation of remdesivir) (Attena et al, 2021)
• GI disturbance (nausea, vomiting, constipation)
• LFT derangement (increased ALT and AST)
• Hypokalaemia
• Acute kidney injury (some controversy over whether the solubility enhancer sulfobutylether β-cyclodextrin sodium (SBECD) in remdesivir formulations may contribute to nephrotoxicity)
• Hypersensitivty reactions

EVIDENCE

In vitro activity against SARS-CoV-2 has been demonstrated (European Medicines Agency, 2020)

Clinical trials of note:

• Wang et al (2020) – small placebo-controlled randomised trial (n=237) that found no significant differnce in time-to-clinicial improvement and was stopped early due to higher rates of adverse effects in the remdesivir group
• Spinner et al (2020) – small randomized open-label trial on the effect of remdesivir versus standard care on clinical status at 11 days in patients with moderate COVID-19 found no difference with a 10-day course of remdesivir but the 5-day course of remdesivir had a statistically significant improvement in clinical status. 
• ACTT-1 trial (Beigel et al, 2020) – a randomized, placebo-controlled, double-blinded trial (n=1062) that showed faster time to improvement with remdesivir, especially when treatment began early after symptom onset.
• WHO SOLIDARITY trial (WHO Solidairty trial Consortium, 2020) –  large open-label randomized adaptive trial (500 centers in 30 countries) that showed no effect of remdesivir on in-hospital mortality or time to discharge.
• DISCOVERY trial – open-label adaptive randomised trial (n=857) showed no difference in mortality, or time-to-improvement outcomes, in severe COVID-19 patients. A subgroup analysis found lower rates of progression to mechanical ventilation or ECMO in the remdesivir group.

Both the Solidarity and Discovery trials had higher rates of steroid co-treatment than ACTT-1. Overall the results of these larger trials suggests there is little role for remdesivir in the treatment of severe COVID19 outside of clinical trials. Proponents of remdesivir argue that it may have a role in very early disease or in the immunosuppressed.

There is uncertainty about relative benefit of 5 or 10 day course (Goldman et al, 2020) – access for longer than 5 day courses requires special consideration in Australia.

OTHER

Only available in Australia through the National Medical Stockpile for 5 day courses – patients must meet the eligibility criteria.

REFERENCES

FOAM and web resources

• Pubchem – Remdesivir
• ACTT-1 – The Bottom Line
• Wang – The Bottom Line

Journal articles

• Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (Discovery): a phase 3, randomised, controlled, open-label trial. The Lancet Infectious Diseases. Published online September 2021:S1473309921004850. [article]
• Attena E, Albani S, Maraolo AE, Mollica M, De Rosa A, Pisapia R, Fiorentino G, Parrella R, Severino S, Russo V. Remdesivir-Induced Bradycardia in COVID-19: A Single Center Prospective Study. Circ Arrhythm Electrophysiol. 2021 Jul;14(7):e009811. doi: 10.1161/CIRCEP.121.009811. Epub 2021 Jun 29. PMID: 34182791; PMCID: PMC8294658. [article]
• Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764. Epub 2020 Oct 8. PMID: 32445440; PMCID: PMC7262788. [article]
• Deb S, Reeves AA, Hopefl R, Bejusca R. ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential. Pharmaceuticals (Basel). 2021 Jul 8;14(7):655. doi: 10.3390/ph14070655. PMID: 34358081; PMCID: PMC8308800. [article]
• European Medicines Agency. Summary on compassionate use: remdesivir Gilead. April 3, 2020. (https://www.ema.europa.eu/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf).
• Fan Q, Zhang B, Ma J, Zhang S. Safety profile of the antiviral drug remdesivir: An update. Biomed Pharmacother. 2020 Oct;130:110532. doi: 10.1016/j.biopha.2020.110532. Epub 2020 Jul 22. PMID: 32707440; PMCID: PMC7373689. [article]
• Goldman JD, Lye DCB, Hui DS, et al; GS-US-540-5773 Investigators. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020 Nov 5;383(19):1827-1837. doi: 10.1056/NEJMoa2015301. Epub 2020 May 27. PMID: 32459919; PMCID: PMC7377062. [article]
• 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;395:1569-1578. [PMC free article]
• WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed Antiviral Drugs for Covid-19 – Interim WHO Solidarity Trial Results. N Engl J Med. 2021 Feb 11;384(6):497-511. doi: 10.1056/NEJMoa2023184. Epub 2020 Dec 2. PMID: 33264556; PMCID: PMC7727327. [article]