Continuing Education Activity

Remdesivir is a broad-spectrum antiviral agent that has previously demonstrated antiviral activity against filoviruses (Ebola viruses, Marburg virus), coronaviruses (SARS-CoV, MERS-Co-V, SARS-CoV-2), paramyxoviruses (parainfluenza type III virus, Nipah virus, Hendra virus, measles, and mumps virus), and Pnemoviridae (respiratory syncytial virus). Remdesivir was shown to exhibit antiviral activity against SARS-CoV-2 in vitro studies, and it was proposed as an investigational drug early during the pandemic. However, based on data from randomized clinical trials that demonstrated superior clinical efficacy of remdesivir to placebo, remdesivir became the first antiviral drug approved by the US Food and Drug Administration (FDA) for clinical use in the management of patients with severe suspected or laboratory-confirmed COVID-19. It is the first drug approved by the US Food and Drug Administration (FDA) for clinical use in hospitalized patients with COVID-19 illness. This activity examines the pharmacology, dosing, indications, contraindications, and adverse events of remdesivir to optimize patient outcomes.

Objectives:

• Review the indication of remdesivir alone or in combination with other drugs.
• Outline the recommended doses for remdesivir in both pediatric and adult patient populations.
• Describe the importance of close monitoring of renal and hepatic function before, during, and after the use of remdesivir.
• Describe the importance of the interprofessional team approach, especially given the limited published literature on this drug's clinical efficacy and safety profile.

Indications

Remdesivir is a broad-spectrum antiviral agent that has previously demonstrated antiviral activity against filoviruses (Ebola viruses, Marburg virus), coronaviruses (SARS-CoV, MERS-Co-V, SARS-CoV-2), paramyxoviruses (parainfluenza type III virus, Nipah virus, Hendra virus, measles, and mumps virus), and Pnemoviridae (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 but failed to demonstrate efficacy in randomized clinical trials.[4][5] Remdesivir was shown to exhibit antiviral activity against SARS-CoV-2 in vitro studies, and it was proposed as an investigational drug early during the pandemic. However, based on data from randomized clinical trials that demonstrated superior clinical efficacy of remdesivir to placebo, remdesivir became the first antiviral drug approved by the US Food and Drug Administration (FDA) for clinical use in the management of patients with severe suspected or laboratory-confirmed COVID-19.

FDA Approved Indication (with clinical trial summaries)

• Adults and pediatric patients (over age ≥ 28 days and weighing  ≥ 3 kgs or more) with a laboratory-confirmed positive  SARS-CoV-2 test who ARE hospitalized patients OR in 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
  • Results of a randomized, open-label trial of hospitalized patients admitted with moderate COVID-19 illness who were randomized to receive a 10-day course of remdesivir(n=197), a 5-day course of remdesivir(n=199), or standard of care(n=200) reported that patient is receiving the 10-day course of remdesivir did not have a statistically significant difference in clinical status compared to patients receiving standard of care. 
  • However, patients randomized to a 5-day course of remdesivir had a statistically significant difference in the clinical status compared to the standard of care.[6]
  • Final results of another double-blind, randomized placebo-controlled trial evaluating the efficacy of remdesivir in hospitalized patients with confirmed SARS-CoV-2 and COVID-19 pneumonia demonstrated that remdesivir was superior to placebo in shortening the time to clinical recovery.[7]
  • However, results from the WHO Solidarity Trial conducted at 405 hospitals spanning 40 countries involving 11,330 inpatients with COVID-19 who were randomized to receive remdesivir (2750), hydroxychloroquine(954), lopinavir(1411), and interferon regimens(2063), and no trial drug(4088) reported that remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on overall mortality, initiation of mechanical ventilation, and length of hospital stay.[8]
  • Based on the encouraging data from three randomized, controlled clinical trials that evaluated the clinical efficacy of remdesivir in patients hospitalized with mild-to-severe COVID-19, the US Food and Drug Administration(FDA) approved remdesivir for treatment in adults and pediatric patients with COVID-19.

• The latest National Institutes of Health (NIH) Covid-19 treatment guidelines panel recommends the use of either remdesivir alone or dexamethasone plus remdesivir or dexamethasone alone if combination therapy (remdesivir and dexamethasone) is not available in hospitalized 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/information

• The efficacy of remdesivir alone or in combination with other drugs has not been evaluated in the SARS-CoV-2 variants- UK variant (B.1.1.7 lineage/VOC 202012/01), South African variant (B.1.351 lineage/501Y.V2), Brazil variant (B.1.1.248/B1.1.28/P1/501Y.V3) and the Californian variant (B.1.427/B.1.429) lineage and clinical trials are ongoing. However, as with any other antiviral drug, there is always a concern about acquiring resistance against mutant viruses.
• The clinical efficacy and safety of remdesivir combined with tocilizumab compared with remdesivir with placebo in hospitalized patients with severe COVID-19 illness; combination therapy did not reduce the time to hospital discharge or "ready for discharge" by day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia.[9]
• Remdesiivr has demonstrated in vitro antiviral activity against the omicron variant (B.1.1.529).[10] A recent study evaluating the effect of available antiviral drugs against COVID-19 that include remdesivir may have therapeutic value against the Omicron subvariants BA.2.12.1, BA.4, and BA.5 as well.[11]

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.[12][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.[13][14][15]

Once remdesivir is metabolized by the host cells into its pharmacologic 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.[13][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).[16][17] 

Data regarding the pharmacokinetics of remdesivir is limited. A randomized, blinded, placebo-controlled, phase I 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 exhibiting similar pharmacokinetic parameters.[18] 

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 its route of administration, and rapid elimination, its potential to cause clinically significant drug-drug interactions (DDIs) may be limited.[19][20] Nevertheless, further clinical studies are required to evaluate its interaction with the cytochrome P450 system, which would determine the potential drug-drug interactions with remdesivir.

Administration

Based on the review of the summary describing the compassionate use of remdesivir published by the European Medicines Agency (EMA,2020), researchers noted that the bioavailability of remdesivir in animal models was poor when administered via the oral route due to almost complete first-pass clearance attributed to poor hepatic stability. Also, the pharmacologic active analog adenosine triphosphate was delayed when administered via the intramuscular (IM) route. However, radiolabeled remdesivir administered intravenously in rats and monkeys demonstrated the widespread distribution of radioactivity in most tissues with the circulation of the predominant metabolite GS-441524. Hence, the conclusion was that the intravenous (IV) administration of remdesivir delivered the active metabolite rapidly compared to the IM or oral route. When administered IV, the absolute bioavailability of remdesivir formulations is 100%, with readily detectable levels of remdesivir in blood and plasma following a single remdesivir infusion in healthy male participants reaching peak concentrations at the end of infusion.[19]

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 f remdesivir, a baseline renal function panel, hepatic function panel, and PT/INR must be performed. If the patient's eGFR is <30mL/min, clinicians should avoid using remdesivir; eGFR >30mL/min requires no dosing adjustments. Hepatic dosing is undefined at present.

Adults and Pediatric Patients Weighing ≥ 40 kg

• 200 mg IV as a loading dose on day 1, followed by a maintenance dose of 100 mg IV every 24 hours for two additional days - the drug should be started ASAP within seven days of symptomatic onset.

Pediatric Patients ≥ 28 days and Weighing  ≥ 3 kgs to <40 kg

• 5 mg/kg/dose IV for a single dose, then 2.5 mg/kg/dose IV every 24 hours for two days - the drug should be started ASAP within seven days of symptomatic onset.

Remdesivir has also received authorization 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 three days.

However, for patients requiring invasive mechanical ventilation and/or ECMO support, treatment may be extended an additional five days. However, for patients not requiring invasive mechanical ventilation and/or ECMO support, remdesivir can be administered for five days with a recommendation to extend treatment duration for five additional days if no clinical response is seen in the first five days, for a total treatment duration of 10 days.

Adverse Effects

Since remdesivir is currently under emergency use authorization, its safety profile has not yet been fully characterized. 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.[18] 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[7]
• Pulmonary: Dyspnea, Acute respiratory failure, acute respiratory distress, pneumothorax, pulmonary embolism
• Hematological: Anemia, lymphopenia[21]
• Endocrine: Hyperglycemia
• Infectious: Pneumonia, septic shock
• Gastrointestinal: elevated lipase, nausea, vomiting, diarrhea, constipation, poor appetite, gastroparesis, and lower GI bleeding[22]
• Hepatic: Hepatic manifestation characterized by Grade 1-4 increase in serum transaminases (ALT and/or AST) are the most common adverse effects in patients treated with remdesivir. Other abnormalities include hyperbilirubinemia[23]
• Renal and Metabolic: Acute kidney injury or worsening of underlying chronic kidney disease, hypernatremia, hypokalemia[24]
• Neurological: Headache, lightheadedness
• Skin: Rash, contact dermatitis, pruritus[25]
• Psychiatric: Delirium[6]
• Other adverse effects: Pyrexia, insomnia,multi-organ dysfunction, DVT, and hypersensitivity/anaphylactic reactions related to the infusion[26]

The above list was compiled from the results of various clinical trials.

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 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 seven days to ≤ 28 days old) with serum creatinine ≥1 mg/dL

Monitoring

Due to limited clinical experience with remdesivir, robust clinical data evaluating the adverse drug reactions and possible drug-drug interactions is limited. Considering that remdesivir is metabolized by cytochrome P450 (CYP450), there is a potential for drug-drug interaction.

RDV 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.[19]

Published data evaluating the safety of remdesivir in pediatric patients (<12 years of age) 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.[27]

 The pharmacokinetics of remdesivir have not undergone assessment in patients >65 years of age. 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. Consideration should be made to check laboratory monitoring before and after the initiation of remdesivir in adults and pediatric patients hospitalized with suspected or laboratory-confirmed COVID-19 infection.

Toxicity

There is a lack of robust 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 serious toxic effects or associated mortality with its clinical use.

Enhancing Healthcare Team Outcomes

Coronavirus disease 2019 (COVID-19), the illness caused by SARS-CoV-2, has overwhelmed many healthcare systems worldwide. Remdesivir is the first and only currently available therapeutic drug 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 physicians across specialties, nurses, and pharmacists who should be aware of the mechanism of action reported, potential side effects, drug-drug interactions, and recommended doses. The patient should receive the fact sheet issued by the US FDA before receiving the drug. There should be close communication between the ordering physician, the pharmacist, and the nurse. Such a holistic approach would lead to the early identification of potential side effects and drug-drug interactions associated with this drug.