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CURRENT STATUS OF REMDESIVIR IN COVID-19 AND ITS PHARMACOKINETIC PROFILE – A SYSTEMATIC REVIEW
8 September 2021
The world has faced many pandemic situation in the past, the recent ones in the 21st century are the SARS CoV in 2002, MERS CoV-2012 and the Ebola in 2014 and now the COVID-19 (or SARS CoV-2), which is found to be originated from the Wuhan province of china. Remdesivir is a potential antiviral agent which was approved for the for the treatment of Ebola had showed a positive result in the initial trial conducted for the treatment in COVID-19. GS-5734 is a broad spectrum antiviral agent which has been repurposed in the treatment of COVID-19. Remdesivir is a molecule manufactured by Gilead sciences with ACTT-1 trial showing favourable results for Remdesivir reducing the mortality of severe COVID-19 patients. The WHO solidarity trial came out with conclusion of Remdesivir failing to reduce the mortality and hospital stay of the patient (with trials showing some mixed results, it is up to the clinician hands in the use of remdesivir in COVID-19). This article is aimed to narrate the journey of remdesivir from its EUA approval to the current clinical practice.
PHARMACOKINETIC PROPERTY OF REMDESIVIR
The bioanalytical procedure used is the tandem mass spectrometry (LCMS). Remdesivir after intravenous administration shows a dose-proportional increase in plasma concentration of healthy adults between the dose 3-225mg. Remdesivir exists in three metabolic form GS-441524 which is a circulating metabolite, GS-704277 which is an intermediate metabolite, GS-443902 which is the active metabolite, GS-441524 has its peak plasma concentration occurs at the end of the infusion and shows a rapid decline the peak plasma concentration. GS-4415244 was achieved at 1.5-2 hours after a 30 minutes infusion of Remdesivir, the protein binding Remdesivir was found to be 88% in the clinical trials. Remdesivir is metabolized to its clinically active metabolite GS-443902 which is a triphosphate nucleoside analogues, the process of metabolism involves hydrolysis with the help of esterase to its intermediate metabolite GS-704277. GS-704277 upon phosramidate cleavage results in an nucleoside analoque monophosphate which on phosphorylation once again produces GS-443902, the active triphosphate metabolite, the dephosphorylation of GS-443902 results in GS-441524 which can be eliminated by the kidneys, the half life of Remdesivir 1 hour but the half life of GS-441524 can be upto 27 hours. A component in Remdesivir known as cyclodextrine is found to be nephrotoxic. Hence, remdesivir is not to be given in patient with reduced eGFR level of < 30ml/min. Resistance with respect to remdesivir the resistance found was similar to that of SARS CoV, MERS CoV which had the same EC50 value. The mutation is directly related to the alteration in RdRp catalytic site or substrate binding pocket but it caused only minor structural alterations.However there was no specific data of SARSCOV-2 resistence to Remdesivir at the time of writing
The major CYP -enzymes involved in the metabolism of Remdesivir are CYP2D6, CYP2C8, CYP3A4 further involvement of P-glucoprotein were also found. Drugs which are strong inhibitors of these CYP enzymes are found to increase the plasma level of Remdesivir while drugs such as rifampicin which act as enzyme inducers have been found to decrease the plasma level of Remdesivir. Remdesivir is not to be given to patient of HCQ since HCQ can reduce the antiviral activity of Remdesivir.
TOXICITY AND SAFETY PROFILE
(GS-5734) Remdesivir is an effective antiviral medication which showed low affinity towards human RNA polymers II which can be significant factor for Remdesivir to have a good safety profile in human during its in preclinical studies in Ebola outbreak. The dose of Remdesivir ranges between 3-225mg and it is found to have no significant toxicities in single dose however during its course of treatment as 200mg loading dose followed by 100mg from day 2 to 10 it is found that remdesivir increases the ALT and AST levels hence it has to be given carefully in patients with liver disease. Remdesivir injection has sulfobutylether-beta-cyclodextrin when combined with Remdesivir during formulation is found to be nephrotoxic. Hence, Remdesivir must not be given to people with eGFR less than 30. Further results of clinical trials have showed hypotension and cardiac arrest. The benefits are weighs the risk of Remdesivir in COVID-19.
Sulfobutylether-beta-cyclodextrin is a molecule used in formulation of Remdesivir lyophilized powder injection. It is found that prolonged exposure of SBECD that is for 5 to 10 days can cause damage to tubules of the kidney. 100 mg of lyophilized powder of Remdesivir contains 3-6 mg of SBECD which well within the daily permissible dose of 250 mg/kg/day. But still remdesivir should not be administered to patient with CrCl less than 30 ml/min.
In various randomised controlled trial conducted so far with Remdesivir, it is found that Remdesivir in combination with Hydroxychloroquine showed a significant raise in AST and ALT levels when compared to others. Thus, it is found that Remdesivir can cause hepatocellular damage. In a case where 3 doses of Remdesivir was given to pregnant woman of 25 years old at the 34 week of gestation with COVID-19 developed intrahepatic cholestasis of pregnancy and caused increase in bile acids.
FORMULATION OF REMDESIVIR
Remdesivir is a sterile lyophilized solid injection which has no preservative added .The dose is 100 mg and it is given with a19 ml sterile water for injection and it has been further diluted with 0.9% saline before IV administration. Regarding the storage condition of Remdesivir it must be stored below 30 degree celsius in case of an 100 mg vial , if it is a 5mg/ml vial which dilution with 0.9% saline must be stored between 2-8 degree celsius. The maximum number of hours it can be stored in room temperature is 4 hours between (20-25) degree celsius and 24 hours if it is stored between 2 and 8 degree celsius.
Current clinical dose of Remdesivir
The current clinical dose of Remdesivir is 200mg IV on day one the loading dose given over one hour followed by 100 mg from day 2-10 given over IV for 1 hour
MECHANISM OF ACTION OF REMDESIVIR
The sequence identity of RNA dependent RNA polymerase between SARS CoV and SARS CoV-2 is found to be 96%. Therefore drugs which were targeting RdRP of SARS CoV are found to be effective in SARSCOV-2. Remdesivir targets RdRP. It is an adenosine C nucleoside analogue. The molecular mass of Remdesivir is 602.6 and its formula is C27H35N6O8P. The active metabolite of remdesivir is GS-443902. Although remdesivir is more active against virus without EXON it can also evade profreeding of EXON and can function as delayed RNA chain terminator. Remdesivir acts in the Vero E6 cells and inhibit viral entry.
THE APPROVAL OF REMDESIVIR
Remdesivir was first discovered in 2014 during the EBOLA outbreak in West Africa .But the discovery of monoclonal antibodies surpassed remdesivir in the phase 3 of clinical trials. But during the discovery of drugs to COVID -19 it is found that Remdesivir can be a potential candidate to it. Remdesivir too showed positive results in the initial clinical trials and gained orphan drug status in March 2020. Then the Gilead sciences entered and requested for the withdrawal of orphan drug status followed by in the month of MAY emergency use authorization was given in US which led to emergency use in many nations such as Japan and Taiwan .In India Remdesivir was given a restricted approval for emergency use in June . Further in the month of July, European Union, UAE, Australia, South Korea and Canada have also given approval for emergency use. In the month of August a new drug application for Remdesivir use in COVID-19 was submitted to the USFDA and finally, the FDA approval was given in October 22, 2020. Gilead Sciences are the manufacturer of Remdesivir (VEKLURY). In India, the manufacturers of remdesivir are Cipla, Heterodrugs, Mylan and Jubilant Pharma.
CURRENT CLINICAL GUIDANCE AND RECOMMENDATIONS OF REMDESIVIR
Currently, Clinical guidance of remdesivir mainly depends upon the oxygen need of patients. In Patients who are not on supplemental oxygen. Remdesivir does not show much of improvement in the SIMPLE TRIAL and there was no further difference between the 5 -10 day treatments of Remdesivir. But incase where the patient are requiring supplemental low flow oxygen both ACTT AND SIMPLE TRIAL showed that remdesivir reduces mortality and hospital stay of the patient. where as in patients who are in need of high flow cannula (or) non invasive ventilation there was a contradiction in the use of Remdesivir in these patients where ACTT trial showed a positive result and SIMPLE TRIAL showed negative outcomes with remdesivir use. In case of patients with mechanical support both studies showed negative results. The SOLIDARITY trial on the other hand does not recommend the use of Remdesivir. Remdesivir is commonly recommended in case where the respiratory rate is less than 30, Spo2 less than 94% , in case of respiratory distress and to patients in intensive care unit. Further guideline such as US national institute of health had given a strong recommendation of use of Remdesivir in severe COVID19, while the Australian National guideline had given a weak recommendation for use of remdesivir in severe COVID-19.
COVID-19 had become a greater challenge to the health care workers, with vaccines getting their emergency use authorisation and drugs getting FDA approved hopefully we will come out with a molecule that can act as a cure for COVID-19. Remdesivir is an effective antiviral medication in spite of trials giving mixed results it had been found that remdesivir is effective in patients requiring external oxygen supply and it also showed no significant difference between 5 day and 10 day regimen of remdesivir. Therefore we are in need of further randomized control trials with respect to remdesivir in order to get a better understanding of the drug and its role in COVID-19. Till then remdesivir is used in COVID-19 treatment based on the clinicians’ opinion.
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