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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 1  |  Page : 1-6

Safety and sagacious use of remdesivir: Paramount focus on contemporary perspectives


Department of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India

Date of Submission01-Aug-2021
Date of Acceptance17-Oct-2021
Date of Web Publication11-Mar-2022

Correspondence Address:
Jeetendra Kumar Gupta
Institute of Pharmaceutical Research, GLA University Mathura, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_161_21

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  Abstract 


The outbreak of COVID-19 has severely impacted the viability on the earth. Its pathogen severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has manifested catastrophic effect on the world's demographics and emerged as the most epizootic agent for human beings. Even though considerable progress in research has led to a better understanding of the virus, there is no specific and potent treatment or cure has been proven effective for this disease. Based on the available scientific evidences, U. S. Food and Drug Administration has issued an emergency use authorization for the emergency use of remdesivir against SARS-CoV-2 virus in critical and hospitalized patients. Remdesivir is a prodrug form of a nucleoside analog GS-441524. It is given intravenously because of its poor absorption through oral route. Remdesivir acts against viral RNA-dependent RNA polymerase targeting viral genome replication. It has been used in many countries as an emergency drug for the treatment of COVID-19 in hospitalized patients. However, in order to substantiate the result through suitable statistics, large-scale clinical trials are required. As per existing studies, the most common adverse effects reported after intravenous administration of remdesivir are elevation in the level of aminotransferase enzymes and bilirubin. Renal impairment, hypotension, and diarrhea have also been revealed in few patients. As of now, there is limited trial data available on remdesivir, so irrevocable epilogues cannot be drawn. However, it is believed by many therapists that irrational use of remdesivir should be prohibited. The erroneous use of remdesivir can lead to the SARS-CoV-2 virus mutating, and its consequence may be ill-starred in future.

Keywords: Antiviral, coronavirus, COVID-19, remdesivir, severe acute respiratory syndrome coronavirus-2


How to cite this article:
Gupta JK. Safety and sagacious use of remdesivir: Paramount focus on contemporary perspectives. Biomed Biotechnol Res J 2022;6:1-6

How to cite this URL:
Gupta JK. Safety and sagacious use of remdesivir: Paramount focus on contemporary perspectives. Biomed Biotechnol Res J [serial online] 2022 [cited 2022 Jul 7];6:1-6. Available from: https://www.bmbtrj.org/text.asp?2022/6/1/1/339361




  Introduction Top


Ethics of medicine is a motif that seeks to explore underlying issues in research, theory, and practice of medicine within the health sciences. Although, in the beginning of any medicinal research, its preliminary screening is carried out on animals, the notion of medicine has always been integral to clinical framework. At present, entire world has gone under COVID-19 pandemic. The virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has gravely wounded human's life with many serious consequences. Research laboratories and hospitals worldwide are scrutinizing many drugs and therapies on COVID-19 carriers to explore a potential treatment. The virus of COVID-19 is SARS-CoV-2 which is a new strain of coronavirus family and initially reported in Wuhan, China. The genome of this virus is composed of positive-sense single-stranded RNA having nearly 30,000 nucleotides.[1] The nature of this virus is fast spreading and extremely virulent. The drugs being investigated for the treatment of this ailment fall into two brackets: Few are targeting viral replication cycle while plentiful are aiming to control the symptoms of this disease.[2] Recent clinical directions of COVID-19 consist of infection prevention agents, control measures, and supportive care.[3],[4] The patients having low risk of progression of disease can be managed by supportive care and symptomatic treatment, while the patients having high risk can be treated under Food and Drug Administration (FDA) emergency use authorization (EUA) criteria with the help of anti-SARS-Cov-2 monoclonal antibodies.[5],[6] As far as the use of anti-viral drugs are concerned, there are insufficient data to support the routine use of those drugs.

Despite many drugs and treatments for COVID-19, there is no proven curative therapy for this illness as of now; however, a broad-spectrum antiviral agent Remdesivir has been recently approved by FDA under EUA for the critical patients of COVID-19.[7],[8],[9] The use of steroidal and nonsteroidal drugs in the treatment has also equivocal status. Some anecdotal reviews support the use of nonsteroidal anti-inflammatory drug during early progression of this disease; however, there is no population-based research manifestation the direct relationship of those drugs with the alleviation of COVID-19. Acetaminophen can only be recommended as anti-pyretic agent to manage the pyrexia associated with COVID-19.[10] In the past, glucocorticoids have been reported for its ill-effects and delayed viral clearance in patients with Middle east respiratory syndrome coronavirus (MERS-CoV) infection.[11] However, recently, the use of dexamethasone has been encouraged in patients of COVID-19 to reduce systemic inflammations.[12],[13] The virus SARS-CoV-2 is a thrombogenic virus.[14],[15] Based on the clinical symptoms and intricacy, many other drugs such as anti-thrombogenic agents have also been preferred to manage the elevated D-dimer level.[16] Scientists worldwide are running various experiments and observations to develop the treatments of COVID-19.[17],[18] The World Health Organization is continuously keeping an eye on this pandemic to get rid of this vicious malady. Several clinical trials are ongoing to treat the patients of COVID-19. The United States FDA has already approved remdesivir under EUA for severely hospitalized adults and children. Although the role of remdesivir in clinical practice has remained ambivalent, it has achieved worldwide curiosity as an assuredly effective moiety and is increasingly being utilized to treat critical patients. The objective of this article is to review and abridge the significant properties of remdesivir, its safety profile, contemporary evidences, and perspectives for the treatment of COVID-19 patients.


  Remdesivir as Neoteric Drug Top


Remdesivir is a claimed for broad-spectrum antiviral agent developed by Gilead Science in collaboration with U. S. Centers for Disease Control and Prevention and the U. S. Army Medical Research Institute of Infectious Diseases. It is a prodrug of monophosphate nucleoside analog (GS-441524) which acts against viral RNA-dependent RNA polymerase (RdRp) enzyme and inhibits viral genome replication. Remdesivir was originally evaluated in the clinical trials against Ebola outbreak in 2014. Upon entry of remdesivir into the host cell, it goes under phosphorylation to produce nucleoside triphosphate (NTP). The metabolite (NTP) competes with adenosine triphosphate (ATP) and inhibits the viral RdRp enzyme activities. In many scientific studies, it has been observed that remdesivir possessed broad-spectrum activity against numerous RNA viruses, such as SARS, MERS, and circulating human coronaviruses (HCoV-OC43 and HCoV-229E).[19],[20] Various mileposts in the development of remdesivir are depicted in [Figure 1].
Figure 1: Mileposts in the introduction of Remdesivir

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  Paramount Evidences in vitro Studies Top


On the basis of existing scientific studies on Ebola virus, remdesivir was also observed for its anti-viral properties by many researchers on different strains of coronavirus.[21],[22] The half-maximal inhibitory concentration (IC50) and half-maximal effective concentration (EC50) were observed through various cell-lines, such as human airway epithelial cells, Cellosaurus (Calu-3 2B4), and African green monkey kidney epithelial cells (Vero E6).

These data demonstrate the prospects of remdesivir against SARS-CoV-2, SARS-CoV, and MERS-CoV strains of coronavirus [Table 1].
Table 1: Evidences in vitro studies of remdesivir against coronaviruses

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  Evidences in vivo Studies Top


Remdesivir was initially evolved as an anti-viral agent against Ebola virus, but recently, it was also demonstrated against MERS-CoV in rhesus macaque model during a pharmacological study.[29] Further remdesivir was also evaluated against Marburg virus and also against other RNA viruses in both mice and nonhuman primates.[30],[31],[32] It was also found effective against feline and bat coronaviruses.[33],[34] In vivo studies of remdesivir on other noncoronaviruses have also been carried out using rhesus monkeys and African green monkeys.[28],[34]

On the basis of several cell lines and animal studies, remdesivir was also tested on human subjects. The antiviral potency of this drug has been observed on human beings in a clinical trial. The study was randomized, double-blind, placebo-controlled and multicentred at ten hospitals. The patients on which that clinical trial was carried out were adults (aged ≥18 years) admitted to hospital with SARS-CoV-2 infection. In that study, it was reported that patients receiving remdesivir had a numerically faster time to clinical improvement with respect to the placebo group, but the result was not associated with statistically significant clinical benefits.[35] Divergent clinical studies and trials are ongoing in many countries.


  Mechanism of Action of Remdesivir Top


Remdesivir was the first drug approved by the United States FDA for the treatment of COVID-19 through an EUA.[36] It is an intravenous monophosphoramidate prodrug. The active form of remdesivir is GS-441524, which is a monophosphate nucleoside analog.[37] Once the drug remdesivir is metabolized by the host cells into its active metabolite (GS-441524), it competes with ATP inside the nascent RNA and forms a complex with viral RdRp enzyme which impedes viral replication inside the host cell [Figure 2].
Figure 2: Active metabolite of Remdesivir inhibits viral RNA-dependent RNA polymerase inside the host cell

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Here, it is evident that the monophosphoramidate nucleoside prodrug remdesivir undergoes metabolic modification inside the host cell and its active metabolite, i.e., NTP has potential propensity to target RdRp. The formation of RdRp–active metabolite (GS-441524) complex halts the activity of viral genome replication inside the host cell.[38] This drug is indicated for the treatment of COVID-19 in hospitalized patients aged 12 years and over whose body weight is not <40 Kg. Irrational use of remdesivir may allow SARS-CoV-2 RdRp mutation in a B-cell immune deficient patient with protracted COVID-19.[39]


  Adverse Events of Remdesivir Top


At present, remdesivir has achieved the level of wide-spectrum antiviral drug against many viruses. It has also emerged as a potential drug candidate for fighting against SARS-CoV-2. However, with increasing clinical application of remdesivir, its adverse effects have been noticed. In this concern, numerous scientific experiments and clinical evaluations have been studied and summarized [Table 2].
Table 2: Adverse effects of remdesivir in coronavirus disease 2019 patients

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In cohort studies of remdesivir in hospitalized patients of COVID-19, many clinicians reported the adverse drug effect where the level of hepatic enzymes and total bilirubin were apparently high, but in those trials, the number of patients exposed to remdesivir was too limited. Although the evidences of nephrotoxicity in Phase-I clinical trials have not been reported, but in many other studies, dose-dependent kidney dysfunction has been reported. Hence, it is worthwhile to measure kidney functions while administering remdesivir in patients with preexisting kidney disease. There was no side effect of this drug was observed on the cardiovascular system when the observation was carried out on monkeys.[45] However, during the clinical studies of remdesivir against Ebola virus, a case of cardiovascular impairment was observed.[46] Few cases of fibrillation and hypernatremia were also observed in China during a randomized controlled trial.[45] In a study carried out by Grein et al., few cases of diarrhea were observed in the recipients of remdesivir.[47] Cases of nausea and vomiting were also reported after the administration of remdesivir.[48]


  Contemporary Evidences and Perspectives in Treatment Top


Remdesivir is recognized as a broad-spectrum antiviral agent which has manifested antiviral activities against many viruses, such as Ebola virus. respiratory syncytial virus (Pneumoviridae), Nipah virus, mumps, and measles virus, Marburg virus and Coronaviruses.[49],[50],[51],[52],[53],[54] It was initially developed against Ebola virus but breakdown to demonstrate efficacy in a randomized clinical trial. Remdesivir was found effective against SARS-CoV-2 in experimental studies, and it was approved by FDA as an EUA in hospitalized patients of COVID-19. The Drug Controller General of India has also ratified remdesivir for restricted emergency use in severely ill patients of COVID-19 on the June 1, 2020.[55] Compassionate use of remdesivir has been demonstrated even in pregnant women, postpartum women, and children with severe COVID-19. However, published data estimating the safety and sagacious uses of remdesivir are sparse.[56],[57],[58] Appraisal should be made to check laboratory monitoring before and after the recommendation of remdesivir in adults and pediatric patients hospitalized with severe infections. Remdesivir is countenanced with a low incidence of adverse events. Most adverse events have been seen in patients with underlying illnesses. Nevertheless, future clinical investigations are required to assess the interaction of remdesivir with cytochrome P450 system which could ascertain the prospects of drug-drug interactions.


  Conclusion Top


Emergence of SARS-CoV-2 (COVID-19) has become a global crisis and sizable challenge of present time. It has induced undue loss of human life worldwide and dispersed a horrible change to public health. The contagion COVID-19 is caused by positive-sense single stranded RNA virus named SARS-CoV-2. The symptoms of this disease range from being asymptomatic or minimal respiratory distress to febrile affliction as well as severe acute respiratory tenderness needing ventilator support. As this pandemic has severely impacted human beings worldwide, scientific communities and pharmaceutical companies have mobilized to develop potential therapeutics and vaccines to control the pandemic. Repurposing of drugs is considered as the fastest way to control the tide of this disease. Studies on remdesivir have shown both in vitro and in vivo activity against SARS-CoV-2 virus. Recently, in preliminary clinical studies, remdesivir led to great clinical improvement in hospitalized patients of COVID-19.

Based on the available evidences, U. S. FDA has issued an EUA for the emergency use of remdesivir in hospitalized COVID-19 patients. It was originally developed by Gilead Sciences in 2009 and used against Ebola virus as well as against Marburg virus. In few in vitro studies, it was found active against coronaviruses, pneumoviruses, and filoviruses. Recently, it has been used as anti-SARS-CoV-2. However, there is limited clinical information known about the safety and effectiveness of remdesivir due to its vulnerable clinical trial. However, with its ameliorative outcome against COVID-19, it is currently in phase-III clinical trial. As per existing scientific data, certain adverse effects have been documented such as drug-induced oxidative stress on the liver and kidney. Since, the virus SARS-CoV-2 is also implicated in the laceration of multiple organs; hence, it is byzantine to distinguish underlying causes of unfortunate events due to remdesivir treatment. As of now, scientific research do not expound any example of remdesivir resistant SARS-CoV-2 strains, however it is predicted by many researchers that irrational use of remdesivir may lead to the SARS-CoV-2 virus mutating, and as a result, the virus may become rugged and resistant for that antiviral drug. The present viral pandemic and its defiance compel us to consider the emergence of potential infectious diseases in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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