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Remdesivir
Indications
Remdesivir is a broad-spectrum antiviral agent that has previously demonstrated antiviral activity against filoviruses (eg, Ebola viruses, Marburg virus), coronaviruses (eg, SARS-CoV, MERS-Co-V, SARS-CoV-2), paramyxoviruses (eg, parainfluenza type III virus, Nipah virus, Hendra virus, measles, and mumps virus), and Pnemoviridae (eg, respiratory syncytial virus).[1][2][3] Remdesivir was initially developed against the Ebola virus based on its antiviral properties demonstrated in vitro and in vivo in animal models. However, it failed to demonstrate efficacy in randomized clinical trials.[4][5]
FDA-Approved Indications
Remdesivir exhibited antiviral activity against SARS-CoV-2 studies in vitro and was initially proposed as an investigational drug early during the COVID-19 pandemic. However, based on data from a multinational, double-blind, randomized placebo-controlled trial that evaluated the efficacy of remdesivir in hospitalized patients with mild, moderate, or severe COVID-19 demonstrated that remdesivir was superior to placebo in shortening the time to clinical recovery, remdesivir became the first antiviral drug to receive approval by the US Food and Drug Administration (FDA) for clinical use in adults and pediatric patients meeting the following criteria:
- Patients 28 days and older and weighing 3kgs or more with a laboratory-confirmed positive SARS-CoV-2 test who are hospitalized
- Patients with mild-to-moderate COVID-19 who are non-hospitalized but are at high risk for progression to severe COVID-19, including hospitalization or death.[6]
- The National Institutes of Health (NIH) COVID-19 treatment guidelines panel currently recommends the use of either remdesivir alone in hospitalized patients who are at high risk of progressing to severe COVID-19 or dexamethasone plus remdesivir or dexamethasone alone if combination therapy (remdesivir and dexamethasone) is not available in patients who require supplemental oxygen but are not receiving HFNC or NIPPV or IMV or ECMO.
Pertinent Studies Against SARS-CoV-2 Variants and Ongoing Trials and Information
The efficacy of remdesivir alone or in combination with other drugs has not been evaluated in the SARS-CoV-2 variants, and clinical trials are ongoing. However, as with other antiviral drugs, there is always a concern regarding acquiring resistance against mutant viruses.
Remdesivir has demonstrated in vitro antiviral activity against the Omicron variant (B.1.1.529).[7] A recent study evaluating the effect of available antiviral drugs against COVID-19, including remdesivir, may also have therapeutic value against the Omicron subvariants BA.2.12.1, BA.4, and BA.5.[8]
Mechanism of Action
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Mechanism of Action
Remdesivir (GS-5734) is a phosphoramidite prodrug of a monophosphate nucleoside analog (GS-441524) and acts as a viral RNA-dependent RNA polymerase (RdRp) inhibitor, targeting the viral genome replication process.[9][5]
Theoretically, nucleoside analogs do not permeate through the cell wall easily. Upon their subsequent entry into the host cell, they require phosphorylation to produce nucleoside triphosphate (NTP), which resembles adenosine triphosphate (ATP) and can be used by the RdRp enzymes or complexes for genome replication.[10][11][12]
Once remdesivir is metabolized by the host cells into its pharmacologically active analog adenosine triphosphate (GS-443902), it competes with ATP for integration by the RdRp complex into the nascent RNA strand and, upon subsequent incorporation of a few more nucleotides, results in termination of RNA synthesis limiting viral replication.[10][5]
Remdesivir demonstrated potent antiviral activity against SARS-CoV-2 in vitro in primary human airway epithelial cultures and human lung cells. Remdesivir also had a dose-dependent inhibitory effect on SARS-CoV-2 replication with a half-maximal effective concentration (EC50).[13][14]
Pharmacokinetics
Data regarding the pharmacokinetics of remdesivir is limited. A randomized controlled study evaluating the pharmacokinetics of single-dose and multiple-dose remdesivir compared to placebo in healthy subjects reported that following single-dose IV administration of remdesivir over 2 hours, remdesivir and its metabolites exhibited a linear profile across the study doses that ranged from 3 to 225 mg with both solution and lyophilized formulations also displaying similar pharmacokinetic parameters.[15]
Remdesivir is a substrate of organic anion transporting polypeptide OATP1B1, OATP1B3, and P-glycoprotein (P-gp) transporters and many cytochrome P450 (CYP450) that include CYP2C8, CYP2D6, and CYP3A4 and is considered to be an inhibitor of CYP enzymes in vitro; however, there has been no evidence of CYP induction by remdesivir and its metabolites in vivo. However, based on the drug's route of administration and rapid elimination, remdesivir's potential to cause clinically significant drug-drug interactions (DDIs) may be limited.[16][17] Nevertheless, further clinical studies are required to evaluate the drug's interaction with the cytochrome P450 system, which would determine the potential drug-drug interactions with remdesivir.
Administration
Adult Dosing
The current recommended dose of remdesivir for adults and pediatric patients hospitalized with suspected or laboratory-confirmed COVID-19 infection is weight-based, and administration is via the IV route. Before initiating remdesivir, a baseline renal function panel, hepatic function panel, and PT/INR must be performed per FDA recommendations. If the patient's eGFR is <30 mL/min, clinicians should avoid using remdesivir; eGFR >30 mL/min requires no dosing adjustments. Hepatic dosing is undefined at present.
Adults and Pediatric Patients Weighing ≥40 kg
- Mild-to-moderate disease: 200 mg IV should be given as a loading dose on day 1, followed by a maintenance dose of 100 mg IV every 24 hours for 2 additional days. The drug should be started ASAP within 7 days of symptomatic onset.
- Severe disease: 200 mg IV as a loading dose on day 1, followed by a maintenance dose of 100 mg IV every 24 hours for 4 additional days. The drug can be given with baricitinib per the FDA Emergency Use Authorization.
Pediatric Dosing
Patients ≥28 days and weighing ≥3 kgs to <40 kg
- Mild-to-moderate disease: 5 mg/kg/dose IV for a single dose, then 2.5 mg/kg/dose IV every 24 hours for 2 days. The drug should be started ASAP within 7 days of symptomatic onset.
- Severe disease not requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 5 mg/kg/dose IV for a single dose, then 2.5 mg/kg/dose IV every 24 hours for 4 days.
Remdesivir has also received approval for use in a non-hospital setting with mild-to-moderate COVID-19 who are non-hospitalized but are at high risk for progression to severe COVID-19, including hospitalization or death, and the optimal treatment duration for COVID-19 is 3 days.
However, treatment may be extended an additional 5 days for patients requiring invasive mechanical ventilation or ECMO support. However, for patients not requiring invasive mechanical ventilation or ECMO support, remdesivir can be administered for 5 days with a recommendation to extend treatment duration for 5 additional days if no clinical response is seen in the first 5 days, for a total treatment duration of 10 days.
Special Patient Populations
Pregnancy considerations: No human data regarding remdesivir during pregnancy or breastfeeding is available. The benefits outweigh the risks in pregnancy.
Breastfeeding considerations: No human data regarding remdesivir during pregnancy or breastfeeding is available. Clinicians must assess the benefit-to-risk ratio for breastfeeding patients.
Adverse Effects
Clinical data about the adverse effects of remdesivir is limited. A randomized, blinded, placebo-controlled, phase I study evaluating the tolerability and safety profile of single-dose and multiple-dose remdesivir compared to placebo in healthy subjects reported that remdesivir was well tolerated in both subjects study groups with no serious adverse effects or associated mortality.[15]
Based on a review of available literature from randomized clinical trials, the following are the potential organ-based adverse effects reported with the use of remdesivir:
- Cardiovascular: Hypotension, arrhythmias, and cardiac arrest [6]
- Pulmonary: Dyspnea, acute respiratory failure, acute respiratory distress, pneumothorax, pulmonary embolism
- Hematological: Anemia, lymphopenia, coagulopathy [18]
- Endocrine: Hyperglycemia
- Infectious: Pneumonia, septic shock
- Gastrointestinal: Nausea is the most commonly reported side effect in patients receiving remdesivir. Other side effects, such as elevated lipase vomiting, diarrhea, constipation, poor appetite, gastroparesis, and lower GI bleeding, have also been reported [19]
- Hepatic: Hepatic manifestations characterized by Grade 1 to 4 increase in serum transaminases (ALT and AST) are the other most common adverse effects in patients treated with remdesivir. Other abnormalities include hyperbilirubinemia.[20]
- Renal and Metabolic: Acute kidney injury or worsening of underlying chronic kidney disease, hypernatremia, hypokalemia [21]
- Neurological: Headache, lightheadedness
- Skin: Rash, contact dermatitis, pruritus [22]
- Psychiatric: Delirium [23]
- Other adverse effects: Pyrexia, insomnia, multi-organ dysfunction, DVT, and hypersensitivity/anaphylactic reactions related to the infusion [24]
Contraindications
Based on the guidance from the documentation published by the European Medicines Agency (EMA, 2020) and U.S FDA issued EUA, remdesivir is contraindicated in the following clinical situations unless the potential benefit of the use of remdesivir outweighs the potential risks:
- Patients with alanine aminotransferase (ALT) levels >5 times the upper limit of normal or severe hepatic dysfunction
- Adult and pediatric patients (>28 days old) with severe renal impairment described as eGFR < 30 mL/min
- Neonates (at least 7 days to ≤ 28 days old) with serum creatinine ≥1 mg/dL
- Hypersensitivity to the drug or any ingredient
Monitoring
Due to limited clinical experience with remdesivir, randomized clinical trials evaluating data evaluating possible drug-drug interactions are currently unavailable. Since remdesivir is metabolized by cytochrome P450 (CYP450), there is potential drug-drug interaction.
Remdesivir is extensively metabolized in the liver by carboxylesterase 1 and primarily eliminated in urine as the nucleoside metabolite GS-441524 based on the results of human mass balance studies.[16]
Published data evaluating the safety of remdesivir in pediatric patients (younger than 12) and pregnant or breastfeeding women are limited. Compassionate use of remdesivir was well tolerated and demonstrated the highest rates of recovery and shortest median time to recovery in pregnant and postpartum women with severe COVID-19.[25]
The pharmacokinetics of remdesivir have not been assessed in patients younger than 65. Nevertheless, given the limited data regarding the safety profile of remdesivir, clinicians should closely monitor for any acute changes in the clinical status of drug-drug reactions. Relevant laboratory panels should be taken before and after the initiation of remdesivir in adults and pediatric patients hospitalized with suspected or laboratory-confirmed COVID-19 infection.
Toxicity
Currently, there is a lack of clinical trial data describing the toxicity associated with remdesivir. However, a randomized, blinded, placebo-controlled, phase I study evaluating the pharmacokinetics, tolerability, and safety profile of single-dose and multiple-dose remdesivir compared to placebo in healthy subjects reported that remdesivir was well tolerated in both study groups with no toxic severe effects or associated mortality with its clinical use.
Enhancing Healthcare Team Outcomes
Remdesivir was the first drug available approved by the US Food and Drug Administration (FDA) for clinical use in managing patients with severe suspected or laboratory-confirmed COVID-19 infection.
Although remdesivir has been approved by the FDA, there is limited published data regarding its long-term adverse effects and interaction with other drugs. Hence, its clinical use in patients hospitalized with COVID-19 illness requires an interprofessional team that includes clinicians across specialties and pharmacists who should be aware of the mechanism of action, potential side effects, drug-drug interactions, and recommended dose of remdesivir.
The patient should receive the fact sheet issued by the US FDA before receiving the drug. Close communication and shared decision-making need to occur between the ordering physician, the pharmacist, and the nursing staff. This interprofessional approach would lead to the early identification of potential adverse effects and drug-drug interactions associated with remdesivir and help patients achieve optimal outcomes.
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