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Remdesivir

Antiviral


(Updated May 13, 2020)



TOP FIVE THINGS TO KNOW ABOUT REMDESAVIR AND OLDER ADULTS¹


  1. Remdesivir is currently being studied as a potential treatment for the outpatient management of Covid-19 infection. Randomized controlled trials are ongoing. 
  2. There are currently no pharmacokinetic data in older adults, and no dosage adjustments based on age.  
  3. Dose modifications are required when renal or hepatic function changes appreciably from baseline.
  4. Although remdesivir may inhibit and/or induce certain CYP450 enzymes, there are no drug-drug interaction studies. 
  5. Because of the potential for additive hepatoxicity, clinical trial participants must abstain from acetaminophen for 14 days after they begin remdesivir.  


Mechanism of Action:   Remdesivir is a prodrug of remdesivir-triphosphate (RDV-TP), an adenosine analog that acts as an inhibitor of RNA-dependent RNA polymerases). RDV-TP competes with adenosine triphosphate for incorporation into nascent viral RNA chains. Once incorporated into the viral RNA, RDV-TP terminates RNA synthesis. Because RDV-TP does not cause immediate chain termination (i.e., 3 additional nucleotides are incorporated after RDV-TP), the drug appears to evade proofreading by viral exoribonuclease (an enzyme thought to excise nucleotide analog inhibitors). Results from initial in vitro testing performed at the China CDC in collaboration with Gilead Sciences showed that remdesivir has potent antiviral activity against SARS-CoV-2 in Vero cells (EC50 = 0.137 M). In another study conducted by the Wuhan Institute of Virology, remdesivir also showed in vitro activity against SARS-CoV-2 in Vero cells (EC50 = 0.77 M).


Compassionate use results for 53 patients recently reported, 30 of whom (57%) were receiving mechanical ventilation and 4 (8%) receiving extracorporeal membrane oxygenation (ECMO). Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. Overall, 17 of 30 patients (57%) receiving mechanical ventilation were extubated, and 3 of 4 receiving ECMO stopped receiving it. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. However, despite these promising signals when compared to historical data of patients receiving ventilation, several caveats are important. First, this is an uncontrolled study, limiting conclusions (essentially a case series). The uncontrolled nature of the study would also obscure any possible signals of harm. Second, the drug was administered a median of 12 days after symptom onset. Since patients typically deteriorate before this point, it is possible that many patients in this series would have improved without the drug. Similarly, 19 patients were not intubated, including 2 patients on room air and 10 patients on low-flow nasal cannula. These patients may have done well regardless of treatment. Third, 7 patients were excluded from the analysis due to an absence of clinical data after the first trial day, and it is unclear what happened to these patients. Finally, it is unclear how these patients were approved for remdesivir, and there is no comparison of patients who applied for the drug and did not receive it in terms of illness severity.


In a randomized, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China, eligible patients were assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2 to 10 in single daily infusions) or the same volume of placebo infusions for 10 days, initiated within 12 days of symptom onset. Eligibility criteria were: aged 18 years, admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. The primary outcome was time to clinical improvement within 28 days after randomization. Clinical improvement was defined as a two-point reduction in patients' admission status on a six-point ordinal scale, or hospital discharge, whichever came first. The six-point scale was as follows: death=6; hospital admission for extracorporeal membrane oxygenation or mechanical ventilation=5; hospital admission for non-invasive ventilation or high-flow oxygen therapy=4; hospital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation)=3; hospital admission but not requiring oxygen therapy=2; and discharged or having reached discharge criteria (defined as clinical recovery—ie, normalisation of pyrexia, respiratory rate <24 breaths per minute, saturation of peripheral oxygen >94% on room air, and relief of cough, all maintained for at least 72 h)=1. The ITT population included 158 patients treated with remdesivir and 78 patients treated with placebo. The median age of study patients was 65 years (IQR 56–71). Overall, median time to clinical improvement was not significantly different in remdesivir group (21 days) vs placebo group (23 days (hazard ratio [HR] 1·23; 95% CI 0·87 to 1·75). 28-day mortality rate was similar in both groups (14 vs 13%). Remdesivir did not result in significant reduction in SARSCoV-2 viral load in nasopharyngeal, oropharyngeal, and sputum samples. Remdesivir was discontinued in 18 pts (12%) because of adverse effects versus four [5%] in the placebo group. Note that study was terminated early because outbreak was in decline, making patient enrolment difficult. It is therefore possible that the study was underpowered.


Dose in Older Adults: No dose adjustments are currently required based on age. However, there are limited data.

Dosing in renal impairment: If the estimated creatinine clearance decreases by more than  50% from baseline, remdesivir should be held and resumed only when the estimated creatinine clearance returns to baseline.

Dosing in hepatic impairment: If ALT and/or AST increase to > 3 times ULN, remdesivir should be held. Dosing may be resumed when the ALT and/or AST returns to baseline. Remdesivir should be stopped and not restarted if:

ALT 3 × ULN and bilirubin 2 × ULN

ALT and/or AST increases to > 5 times ULN

Drug interactions: Remdesivir is a weak inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Remdesavir has also been shown to induce expression of CYP1A2 and CYP2B6 by 5.7-fold and 5.4-fold, respectively. Remdesivir did not inhibit P-gp at the highest concentration tested (40 M), but inhibited OATP1B1 and OATP1B3 with IC50 values of 2.8 and 2.1 M, respectively. However, detailed pharmacokinetic studies of drug interactions are lacking.

Pharmacodynamic drug interactions: Concomitant use of acetaminophen may increase the risk of hepatoxicity. In clinical trials, participants must abstain from acetaminophen for 14 days after they begin remdesivir.

Adverse Effects:
Transaminase elevations +/- mild, reversible PT prolongation (usually no clinically important change in INR) and infusion related hypotension.


Contraindications: Exclusion criteria from clinical trials: 

  • Evidence of multi-organ failure
  • Need of inotropic agents
  • Creatinine clearance < 30 ml/min, dialysis, or hemofiltration
  • Transaminases > 5X ULN
  • Concomitant use of lopinavir/ritonavir

Monitoring Parameters
Presently only available through clinical trials. Monitoring includes renal and hepatic function.


Pharmacokinetics
Absorption: N/A; drug given as intravenous

Distribution:³ Protein binding ~88%.

Metabolism:³ Substrate of CYP2C8, CYP2D6, and CP3A4, OATP1B1 and P-gp. Drug manufacturer claims that metabolism is likely to be predominantly mediated by hydrolase activity.

Elimination half-life:³ 69 minutes

Excretion:³ Mostly recovered in urine (74% of dose) as parent drug and metabolites. Substrate of p-glycoprotein and OATP1B1.

Pharmacokinetics in renal impairment:³ No studies.

Pharmacokinetics in liver disease:³ No studies.


References:
  1. European Medicines Agency. Remdesivir: Summary on Compassionate Use. April 2020.
  2. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10. doi: 10.1056/NEJMoa2007016. [Epub ahead of print]
  3.  Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial. Lancet. 2020; Apr 9. Epub.  DOI: 10.1016/S01406736(20)31022-9

COVID-19 is an emerging, rapidly evolving situation. Get the latest from CDC: https://www.coronavirus.gov and NIH: https://www.nih.gov/coronavirus  and the Liverpool drug interaction group: http://www.covid19-druginteractions.org

This document is for informational purposes only and is not intended as, and should not be interpreted as, medical advice or other professional advice. Clinical judgement is still required. GeriMedRisk does not endorse the use of any of these therapies for COVID, but offers this information in the hopes of decreasing the risk of harmful drug-drug interactions or adverse drug events. We will do our best to update this information.


Last updated: May 13, 2020 10:54 AM                                                                                                                                                                                                       Back to COVID-19 Resources