Remdesivir

by Editorial Board last updated 2020-11-30 15:18:08.440236-05:00 © Antimicrobial Therapy, Inc.
Veklury
  • Remdesivir is FDA approved (Oct 2020) for adults and pediatric patients (age ≥12 years,  weight ≥40 kg) for the treatment of COVID-19 requiring hospitalization. It should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care. Package insert here.
    • Remdesivir is a monophosphoramidate nucleoside prodrug that has a broad antiviral spectrum including filoviruses, paramyxoviruses, pneumoviruses, hemorrhagic fever viruses (Ebola, Marburg), and coronaviruses, including MERS, SARS, and SARS CoV-2.
    • Rapidly converted after IV administration to an alanine metabolite (GS-704277) and then a nucleoside monophosphate intermediate (GS-441524) by non-CYP enzymes. GS-441524 is converted by intracellular kinases to the active triphosphorylated metabolite GS-443902, which acts as an analog of adenosine triphosphate and competes for incorporation into nascent RNA chains by SARS-CoV-2 RNA-dependent RNA polymerase.
    • GS-441524 is the predominant circulating metabolite.
  • HHS Update 10/01/20: full commercial availability through Amerisource Bergen as distributor for Gilead
  • Efficacy of 5-day and 10-day courses of Remdesivir similar for patients with severe COVID not requiring mechanical ventilation (N Engl J Med, May 27, 2020, doi: 10.1056/NEJMoa201530).
  • Safety and efficacy for the treatment of COVID-19 clinical trials:
    • NIAID "Adaptive Treatment Trial" (results reported N Engl J Med online 22 May 20)
      • Superior to placebo in shortening time to recovery in hospitalized adults
      • The study evaluated 1063 COVID-19 patients with advanced disease 
      • DSMB met and determined Remdesivir "was better than placebo from the perspective of the primary endpoint, time to recovery"
      • Remdesivir was associated with a 31% faster time to recovery than  placebo (p<0.001)
      • Median time to recovery was 11 days for patients treated with Remdesivir vs 15 days in the placebo group.
      • A trend toward a survival benefit was noted:  mortality rate of 8.0% for Remdesivir vs 11.6% for placebo (p=0.059).
    • Gilead "SIMPLE" Trial (results via Press Release)
      • Evaluated 5 days vs 10 days of Remdesivir among 397 patients with severe manifestations of COVID-19
      • Similar outcomes were noted in the 5 day Rx group (OR: 0.75; 95% CI 0.51 - 1.12)
      • Time to treatment improvement in 50% of subjects was 10 days (5 day Rx Group) vs 11 Days (10 day Rx Group)
      • At day 14, Clinical Recovery was achieved in 64.5% in the 5 day Rx Group vs. 53.8% in the 14 day Rx Group
      • Adverse Events include:  Nausea (10%), Respiratory Failure (10%), ALT elevations (3 - 7%).
    • Hubei, China Study (Lancet 2020;395(10236):1569)
      • 237 patients with Advanced COVID-19 disease randomized 2:1 to receive Remdesivir vs placebo
      • No difference in overall time to clinical improvement for Remdesivir (HR 1.23, 95% CI 0.87 - 1.75)
      • Trend toward shorter time to clinical improvement among subjects with shorter duration of symptoms (< 10 days); HR 1.52, 95% CI 0.95 - 2.43)
      • No mortality difference in the two groups; more AEs resulting in treatment discontinuation in Remdesivir group (12% vs 5%)
      • No difference in reduction in SARS-CoV-2 viral load by quantitative PCR in the upper respiratory tract; in a subset of subjects with specimens from the lower respiratory tract, the Remdesivir group showed no significant difference at day 5 from placebo, but a slightly more rapid decline in viral load (p=0·0672).
  • Usage
    • Determine eGFR before dosing
    • Hepatic testing should be performed before and during therapy
  • Adult dosing (weight ≥40 kg): 200 mg IV loading dose, then 100 mg IV daily
    • Infuse each dose over 30-120 min.
    • Reconstituted lyophilized powder should be diluted in 100 mL or 250 mL of NS for infusion. Dilute the injection solution in 250 mL of NS (total volume). Compatibility with infusion solutions other than NS is not known.
    • 10 day course for patients on mechanical ventilation/ECMO.
    • 5 day course if not on ventilation/ECMO. If no clinical improvement at 5 days, extend to 10 days.
  • FDA-approved dosing, age ≥12 years, weight ≥40 kg
    • 200 mg IV loading dose, then 100 mg IV daily
  • Age <12 years, weight 3.5-40 kg (under the EUA)
    • 5 mg/kg loading dose, then 2.5 mg/kg IV daily.
    • Infuse each dose over 30-120 min.
    • 10 day course for patients on mechanical ventilation/ECMO.
    • 5 day course if not on ventilation/ECMO. If no clinical improvement at 5 days, extend to 10 days.
  • Not evaluated, but not recommended in adults and pediatric patients (>28 days old) with eGFR <30 mL/min, or in full-term neonates  (≥7 days and ≤28 days) with serum creatinine ≥1 mg/dL, because the excipient sulfobutylether-β-cyclodextrin (SBECD) accumulates in patients with reduced renal function.
  • For eGFR ≥30 mL/min, no adjustment needed.
  • Note that 100 mg of lyophilized powder or injectable solution of Remdesivir contain 3 gm and 6 gm of SBECD, respectively, compared to the maximum recommended safety threshold of 250 mg/kg/day for SBECD. Although conclusive safety data in patients with eGFR <30 mL/min are lacking, the recommended 5-10 day RDV treatment duration and relatively low concentrations of SBECD suggest benefit may outweigh risk, particularly since SBECD is readily removed by hemodialysis and CRRT (J Am Soc Nephrol 2020;31:1384).
  • Pharmacokinetics have not been evaluated in patients with hepatic impairment.
  • Contraindications
    • Known hypersensitivity reaction
  • Warnings (limited clinical data)
    • Infusion related reactions
      • Hypotension
      • Nausea, vomiting
      • Diaphoresis
      • Shivering
    • Increased ALT
  • Serious AEs
    • Increased ALT
    • Liver toxicity, see Major Drug Interactions, below
    • Case of marked sinus bradycardia: JACC Case Rep 2020;2:2260.
  • In vitro activity against:
    • Filoviruses
    • Paramyxoviruses
    • Pneumoviruses
    • Hemorrhagic fever viruses (Ebola, Marburg)  
    • Coronaviruses, including
      • MERS
      • SARS
      • SARS CoV-2
Class  Nucleoside analogue
PK/PD Index  No data
Pharmaceutical
Preparation
 Lyophilized powder, 100 mg per vial
Injection solution, 100 mg/20 mL per vial
Usual Adult Dose  200 mg IV load, then 100 mg IV q24h x5-10 days
Pregnancy
Category
Use only if potential benefit
justifies potential risk to mother and fetus
Food Effect1 Not applicable
Oral
Absorption2 (%)
 Not applicable
Peak Serum Level3
(μg/mL)
Remdesivir: 2.23 (SS)
GS-441524: 0.14 (SS)
Protein Binding
(%)
Remdesivir: 88-93.6
GS-441524: 2
Average Serum
Half-life4 (hr)
Remdesivir: 1
GS-441524: 27
GS-441524 intracellular t1/2 ≈40
Elimination Major route of elimination for GS-441524: glomerular filtration, active tubular secretion
Biliary Penetration5 (%)  No data
CSF/Blood
Penetration6 (%)
 No data
Therapeutic Levels in CSF7  No data
Volume of Distribution8
(Vd)
 No data
AUC249
(μg*hr/mL)
 Remdesivir: 1.56
GS-441524: 2.23
CYP450, Transporter
Interactions
(in vitro data)
Remdesivir: substrate for 3A4, PGP, OATP1B1.
GS-704277: substrate for OATP1B1/B3.
Remdesivir: inhibits 3A4, OATP1B1/B3, MATE1.
  • Notes:
    • 1 Adult preparations unless otherwise noted.
    • 2 Absorption under optimal conditions.
    • 3 Total drug; adjust for protein binding to determine free drug concentration.
      • SD = after single dose
      • SS = steady state after multiple doses
    • 4 Assumes CrCl > 80 mL/min
    • 5 Peak concentration in bile/peak concentration in serum x 100
    • 6 CSF levels with inflammation
    • 7 Judgment based on drug dose & organism susceptibility. CSF concentration ideally ≥10x above MIC.
    • 8 Volume of Distribution (Vd):
      • V/F = Vd/oral bioavailability
      • Vss = Vd at steady state
      • Vss/F = Vd at steady state/oral bioavailability
    • 9 Area under the plasma concentration versus time curve
  • A critically ill COVID-19 patient developed liver toxicity five days after initiation of Remdesivir therapy. Two days after beginning Remdesivir he was also administered amiodarone for new onset atrial fibrillation, and he had recently received a five-day course of chloroquine (last dose nine days before beginning Remdesivir). Remdesivir is a P-glycoprotein (PGP) substrate, and amiodarone and chloroquine inhibit PGP. It is possible that this case of presumed Remdesivir hepatotoxicity was fostered by a drug-drug interaction that raised hepatocellular concentrations of Remdesivir above the toxicity threshold (Clin Infect Dis 2020 Jun 28 [Epub ahead of print]).
  • Due to antagonism observed in cell culture, concomitant use of Remdesivir with chloroquine or hydroxychloroquine is not recommended.
  • Human drug-drug interaction trials have not been conducted. However, the short plasma half-life of Remdesivir suggests a limited potential for clinically relevant drug-drug interactions.
  • Remdesivir vials contain no preservative and are therefore single-use.
  • Diluted infusion in infusion bags is stable for 24 hours at room temperature (20-25ºC) and 48 hours if refrigerated (2-8ºC).
  • Storage:
    • Vials of lyophilized powder: below 30ºC until required for use.
    • Vials of injection solution: refrigerated (2-8ºC) until required for use.