Remdesivir

by Editorial Board last updated 2020-07-08 16:59:22.451395-04:00 © Antimicrobial Therapy, Inc.
  • Remdesivir (GS-5734) is a monophosphoramidate prodrug of a nucleoside (adenosine) analogue (GS-441524) 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 intermediate alanine metabolite (GS-704277) and then GS-441524 by non-CYP enzymes. GS-441524 is converted by intracellular kinases to the active triphosphorylated metabolite GS-443902.
  • 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 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 (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
    • Liver toxicity, see Major Drug Interactions, below
  • 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  200 mg IV x1, 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: 2.61 (SS)
GS-441524: 0.14 (SS)
Protein Binding
(%)
Remdesivir: approx 88
Average Serum
Half-life4 (hr)
Remdesivir: 0.9
GS-441524: 25.3
GS-441524 intracellular t1/2: approx 40
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
Substrate of: 2C8, 2D6, 3A4, PGP, OATP1B1
Inhibitor of: 3A4, OATP1B1/B3, BSEP, MRP4, NTCP
(in vitro data for remdesivir)
  • 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. PGP is an efflux transporter present in the intestine, liver, and kidney; in the liver it transports drug molecules from the hepatocyte into the bile for excretion. It is thus 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]).
  • Human drug-drug interaction trials have not been conducted.
  • The short plasma half-life of Remdesivir suggests a limited potential for clinically relevant drug-drug interactions. Quality data regarding the effect of GS-704277 and GS-441524 on CYP enzymes and transporters are lacking.
  • Studies still underway