Remdesivir

by Editorial Board last updated 2020-05-29 11:07:13.266513-04:00 © Antimicrobial Therapy, Inc.
  • Remdesivir (also GS-5734) is a monophosphoramidate prodrug of a nucleoside (adenosine) analogue that has a broad antiviral spectrum including filoviruses, paramyxoviruses, pneumoviruses, hemorrhagic fever viruses (Ebola, Marburg), and coronaviruses, including MERS, SARS, and SARS CoV-2. 
  • COVID-19: U.S. FDA Emergency Use Authorization 05/01/2020 (See provider Fact Sheet & EUA full prescribing information)
  • 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 are being evaluated in multiple ongoing Phase 3 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 Rx'd 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, ePublished ahead of print, 29 April 2020)
      • 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 (EUA)
    • Determine eGFR before dosing
    • Hepatic testing should be performed before and during therapy
  • Adult dosing (wt > 40 kg): 200 mg IV loading dose on day 1, then 100 mg IV daily maintenance dose
    • 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
  • Pediatric dosing (wt 3.5 - 40 kg): 5 mg/kg loading dose on day 1, then 2.5 mg/kg daily maintenance dose
    • 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,
  • Unknown need for adjustment.
  • Pharmacokinetics not evaluated in patients with hepatic impairment.
  • Unknown / Pending
  • Contraindications
    • Known hypersensitivity reaction
  • Warnings (limited clinical data)
    • Infusion related reactions
      • Hypotension
      • Nausea, vomiting
      • Diaphoresis
      • Shivering
    • Increased ALT
  • Serious AEs
    • Increased ALT
  • 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, single-dose vials
Injection solution, 5 mg/mL, single-dose vials
Usual Adult Dose  See above
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)
4.4 (200 mg IV SD)
Protein Binding
(%)
Approximately 88
Average Serum
Half-life4 (hr)
 0.9
Biliary Penetration5 (%)  No data
CSF/Blood
Penetration6 (%)
 No data
Therapeutic Levels in CSF7  No data
Volume of Distribution8
(Vd)
 No data
AUC9
(μg*hr/mL)
 2.86 (200 mg SD)
CYP450, Transporter
Interactions
Substrate of: 2C8, 2D6, 3A4, PGP, OATP1B1
Inhibitor of: 3A4, OATP1B1/B3, BSEP, MRP4, NTCP
(in vitro data only)
  • 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
  • Human drug-drug interaction trials have not been conducted.
  • Studies still underway