key: cord-346787-uo8k6qic
authors: Jorgensen, Sarah CJ; Kebriaei, Razieh; Dresser, Linda D
title: Remdesivir: Review of pharmacology, pre‐clinical data and emerging clinical experience for COVID‐19
date: 2020-05-23
journal: Pharmacotherapy
DOI: 10.1002/phar.2429
sha: 
doc_id: 346787
cord_uid: uo8k6qic

The global pandemic of novel coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has created an urgent need for effective antivirals. Remdesivir (formerly GS‐5734) is a nucleoside analogue pro‐drug currently being evaluated in COVID‐19 clinical trials. Its unique structural features allow high concentrations of the active triphosphate metabolite to be delivered intracellularly and it evades proofreading to successfully inhibit viral RNA synthesis. In pre‐clinical models, remdesivir has demonstrated potent antiviral activity against diverse human and zoonotic β‐coronaviruses, including SARS‐CoV‐2. In this article we critically review available data on remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics and in vitro activity against coronaviruses as well as clinical experience and current progress in COVID‐19 clinical trials.

The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an urgent need for effective antivirals. 1, 2 A wide variety of novel and repurposed agents are currently being evaluated in clinical trials and anecdotal reports of off-label and compassionate use of a number of these agents have emerged. 3, 4 Remdesivir (formerly GS-5734) is a monophosphoramidate nucleoside analogue prodrug that was originally developed in response to the 2014 -2016 Ebola outbreak in West Africa. 5, 6 ribavirin against coronaviruses, for example, has been attributed to its removal by ExoN. 11 Remdesivir is more active against viruses lacking ExoN but is able to partly evade proofreading and maintain potent antiviral activity in the presence of ExoN. This was nicely illustrated in a βcoronavirus murine hepatitis virus (MHV) model. 11 Compared to wild-type MHV (EC 50 0.087 μM), viruses lacking ExoN were approximately 4-fold more sensitive to remdesivir inhibition (EC 50 0.019 μM). The reason remdesivir's activity is only modestly decreased by ExoN relates to two unique properties. First, remdesivir is incorporated into replicating RNA more efficiently than natural nucleotides. 10, 12, 13 This was shown in a series of kinetic studies that determined the selectivity of βcoronaviruses for remdesivir vs. natural nucleotides. 10, 12 In this context selectivity was defined as the ratio of the parameters Vmax (reflecting the maximal velocity of nucleotide incorporation) to Km Interestingly, selectivity values were higher for Ebola virus (4) and for other nucleotide analogues with SARS-CoV-2 (favipiravir = 570 and ribavirin >> 1000). 10 The second reason that remdesivir is able to partly evade ExoN is because it functions as a nonobligate or delayed RNA chain terminator. 10, 12, 13 Delayed chain termination occurs when a nucleotide analogue has a free 3'-OH group required for the addition of natural nucleotides. The incorporation of the delayed chain terminator however perturbs the RNA structure and synthesis is halted at some point downstream. 13 In SARS-CoV-1, SARS-CoV-2 and MERS-CoV, remdesivir (GS-443902) incorporation consistently results in chain termination after three additional nucleotides are added. 10, 12 It is thought that these nucleotides provide protection from ExoN excision. 10, 12 

As described in the chemistry and pharmacology section, remdesivir is a pro-drug; concentrations decline rapidly after IV administration (plasma half-life, T ½ ~ 1 hour), followed by the sequential appearance of the intermediate alanine metabolite GS-704277 and the nucleoside monophosphate metabolite GS-441524 (plasma T ½ 24.5 hours) ( Figure 1 ). Inside cells, GS-441524 is rapidly converted to the pharmacologically active triphosphate analogue, GS-443902 which has a prolonged intracellular T ½ (peripheral blood mononuclear cell, PBMC T ½ ~ 40 hours). Both remdesivir and GS-441524 exhibit linear PK following single doses between 3 mg and 225 mg and no remdesivir Accepted Article accumulation was observed following once daily dosing for up to 5 days. By contrast, GS-441524 reaches steady state around day 4 and accumulates by ~ 2-fold after multiple once daily dosing. 3 The remdesivir dosing regimen being evaluated in clinical trials (200 mg IV on day 1, then 100 mg IV on days 2 through 5 or 10) was substantiated by in vitro data and bridging the PK with the rhesus monkey experience to humans. 7, 8, 14 Table 1 summarizes pertinent PK parameters of remdesivir and metabolite GS-441524, which were derived from single and multiple-dose studies in healthy human adult volunteers. 14 As shown, remdesivir C max values are many fold above concentrations required in vitro to inhibit SARS-CoV-2 replication by 50% and 90% (EC 50 0.137 -0.77 μM, EC 90 1.76 μM, see microbiology section). 14, 15 Due to the near complete first pass effect of phosphoramidates, remdesivir is expected to have poor oral bioavailability. 6 Plasma protein binding for remdesivir is moderate (free fraction of 12.1%). By contrast metabolites GS-704277 and GS-441524 exhibit low plasma protein binding with mean free fractions ≥ 85%. 14 In cynomolgus monkeys, radiolabeled remdesivir or its metabolites were detectable in the testes, epididymis, eyes and brain 4 hours after a 10 mg/kg dose (equivalent to 200 mg in humans). 16 Levels in the brain were significantly lower than other tissues but accumulated over time. 16 Distribution studies in humans have not yet been reported.

Remdesivir is a substrate of several cytochrome P450 enzymes in vitro (see drug interactions section), however clinical implications are unclear since the pro-drug is rapidly metabolized by plasma hydrolases. 14 By similar reasoning, the effect of hepatic impairment on remdesivir plasma levels should be low although specific studies have not been conducted in patients with hepatic impairment and the drug is contraindicated in patients with severe hepatic impairment. 14 Metabolism of metabolites GS-704277, GS-441524 and GS-443902 has not been characterized.

Remdesivir exhibits low renal excretion (< 10%). However, 49% of a radiolabeled dose was recovered as GS-441524 in urine. 14 Theoretically, plasma exposure of GS-441524 may be increased in patients with renal impairment. Remdesivir formulations contain sulfobutylether β-cyclodextrin sodium (SBECD) as a solubility enhancer. 14 Formulations containing SBECD have historically been cautioned against in patients with renal impairment although clinical data suggest SBECD accumulation does not increase the risk of acute kidney injury. 17 There are no recommendations for dose adjustments in patients with mild to moderate renal impairment at this time. Under the FDA emergency use authorization guidance, remdesivir is not recommended in patients with an estimated Accepted Article glomerular filtration rate (eGFR) < 30 mL/min or serum creatinine ≥ 1 mg/dL unless the potential benefit outweighs the potential risk. 18 Patients with an eGFR < 30 mL/min and those who are receiving hemodialysis or hemofiltration are excluded from the EMA compassionate use program. 14 There are no PK data available for children or women who are pregnant or breast feeding.

Remdesivir has demonstrated broad-spectrum activity against a diverse panel of zoonotic and clinically relevant human coronaviruses including SARS-CoV-1, SARS-CoV-2 and MERS-CoV with micromolar EC 50 or IC 50 values in multiple in vitro systems. 3, 9, 11, 19, 20 In human airway epithelial cell cultures for example, remdesivir inhibited SARS-CoV-1 and MERS-CoV replication with IC 50 values of 0.069 and 0.074 μM, respectively. 9 Emerging data suggests remdesivir also exhibits potent activity against SARS-CoV-2. 14, 15, 21 In testing performed by the Chinese CDC in collaboration with the manufacturer, Gilead Sciences, Inc., using Vero E6 cells (a cell line from green monkey kidney epithelial cells that is commonly used to evaluate antiviral activity), the EC 50 value was 0.137 μM against SARS-CoV-2. 14 14, 15 in this study viral load was fitted in logarithm scales (log 10 TCID 50 /mL and log 10 viral RNA copies/mL). Using this scale EC 50 values were many fold higher at 23.15 μM and 26.90 μM, respectively. 21 It is uncertain which method is most reflective of activity in vivo. It should also be remembered that EC 50 and IC 50 values represent a single point on the dose-response curve and the slope of the curve may be more important when evaluating potency. 22 This relationship is generally neglected when assessing in vitro antiviral activity. Furthermore, clinical outcomes may depend on whether > 90% inhibition is achieved but EC 90 values are reported in a minority of studies.

It is reassuring that the EC 90 value reported by Wang and colleagues (1.76 μM) is achievable with the dosing regimen under evaluation (see PK section). 14, 15

The development of remdesivir resistance in coronaviruses has been assessed by cell culture in MHV which has similar EC 50 values to SARS-CoV-1, SARS-CoV-2 and MERS-CoV. 11 Following > 20 Accepted Article in vitro passages, two nonsynonymous mutations were selected in the nsp12 RdRp: F476L and V553L. Neither of the mutations directly altered RdRp's catalytic site or substrate binding pocket but they did cause minor structural alterations that are thought to impact RdRp's fidelity checking step before catalysis. 11, 13 Compared to wild-type virus, these mutations conferred 2.4-fold and 5-fold reduced susceptibility to remdesivir, respectively while the double mutant showed 5.6-fold reduced susceptibility in vitro. 11 The EC 50 values of the mutants (0.057 -0.13 μM) however, remained below achievable human drug exposures. 3, 11, 13 Furthermore, the mutations appear to confer a fitness cost, with wild-type virus rapidly outcompeting the mutants in the absence of remdesivir. Of concern however, the affected residues are conserved across coronaviruses raising the possibility of a common pathway to resistance. In fact, substitutions at homologous SARS-CoV-1 residues conferred a 6-fold decrease in susceptibility to remdesivir (EC 50 0.01 μM → 0.06 μM). 11 No data specific to SARS-CoV-2 remdesivir resistance have been published at the time of writing.

Remdesivir's efficacy against respiratory diseases caused by β-coronaviruses has been evaluated in both rodent and rhesus monkey models. 7-9, 14, 19 Before summarizing these studies the reader should be aware that rodent models are not ideal for evaluating remdesivir efficacy against β-coronaviruses. First, high levels of serum esterases rapidly degrade the pro-drug (T ½ ~ 5 minutes). 9, 16 Investigators have attempted to overcome this by using esterase knock-out mice. 9 This improves plasma stability (T ½ ~25 minutes), but tissue levels of active metabolites are still ~ 10-fold lower. 9 Second, the active triphosphate metabolite (GS-443902) has a significantly shorter T ½ in the mouse lung (3 hours) compared to human lung cells and nonhuman primate lungs (T ½ 20 -40 hours). 9, 14 Finally, mice are naturally resistant to infection by MERS-CoV due to the inability of the spike protein binding domain to interact with the mouse DPP4 receptor. Therefore transgenic mice harboring a modified humanized DPP4 must be used. 19 These limitations notwithstanding, Sheahan and colleagues evaluated prophylactic and therapeutic remdesivir against SARS-CoV-1 in an esterase-deficient mouse model. 9 Compared to control mice, prophylactic administration of remdesivir (24 hours before viral inoculation) resulted in less weight loss, lower viral lung titers and reduced SARS-CoV-1-induced lung pathology. 9 Similarly, therapeutic remdesivir (administered 1 day post-inoculation) significantly diminished weight loss and viral load and improved pulmonary function, although to a lesser degree than the prophylactic regimen. When

This article is protected by copyright. All rights reserved remdesivir was initiated 2 days post-infection however, it did not improve disease outcomes even though viral lung titers were reduced. The disease course in mice is accelerated compared to humans with viral titers peaking around day 2 concurrent with maximal damage to lungs.

The same group of investigators conducted a similar study evaluating remdesivir and lopinavir/ritonavir +/-interferon-β against MERS-CoV in an esterase-deficient, humanized DDP4 mouse model. 19 Prophylactic remdesivir significantly improved MERS-CoV-induced weight loss, decreased viral lung titers, and diminished features of acute lung injury compared to control mice. It also prevented mortality in mice administered a lethal dose of virus. In contrast, prophylactic lopinavir/ritonavir +/-interferon-β slightly reduced viral loads but had no impact on other disease outcomes. Therapeutic remdesivir also led to improved disease outcomes and lower viral loads, but again, the effect size was diminished compared to prophylactic administration. Remdesivir administered after a lethal viral dose was given (as opposed to before with prophylaxis), did not prevent mortality. 19 The prophylactic and/or therapeutic efficacy of remdesivir has been evaluated in MERS-CoV-infected and SARS-CoV-2-infected rhesus monkeys. These models more accurately recapitulate the lung disease observed in humans with mild-moderate MERS-CoV and SARS-CoV-2 infection compared to rodent models. 23, 24 Dosing and pharmacokinetic analyses can also serve as a bridge to human dosing regimens. 7 However, due to the acute and accelerated infection course in monkeys, it is difficult to directly translate the timing of drug initiation to corresponding disease stages in humans. 23, 24 Furthermore, neither model replicates many of the extrapulmonary disease manifestation seen in humans. 23, 24 In the MERS-CoV study, monkeys were administered remdesivir (5mg/kg which approximates drug exposures equivalent to 100mg in humans) 24 hours before MERS-CoV inoculation (prophylaxis) or 12 hours post-inoculation (treatment). 8 Viral titers peak shortly after 12 hours in this model. For both groups, remdesivir was continued once daily until 6 days post-inoculation. Prophylactic and therapeutic remdesivir treatment significantly reduced MERS-CoV-induced clinical signs, viral titers in respiratory specimens and the severity of lung lesions compared to control animals. These effects were most pronounced in the prophylactic group. 8 A similar prophylactic study was conducted using a higher remdesivir dose (10mg/kg which approximates drug exposures equivalent to 200mg in humans). 14 Clinical signs and viral loads were significantly reduced vs. controls. Increases in serum Accepted Article creatinine and blood urea nitrogen suggestive of altered renal function were only observed in remdesivir treated animals. 14 In the SARS-CoV-2 study, remdesivir was again initiated shortly before viral titers are expected to peak at 12 hours post-inoculation and a dosing regimen equivalent to the regimen being tested in human COVID-19 clinical trials was used (10 mg/kg load ~ 200 mg in humans, then 5 mg/kg daily ~ 100mg daily in humans x 6 days). 7 Compared to vehicle-treated monkeys, remdesivir-treated monkeys had improved clinical and radiographic outcomes. Viral titers were reduced in lower respiratory tract specimens and undetectable at 3 days post inoculation. Viral titers were not reduced in upper respiratory tract specimens nor in rectal swabs however. 7 If translated in humans, the absence of a reduction in viral shedding in these sites may have implications for potential transmission risk following clinical improvement. 7

Initial experience with remdesivir in patients with COVID-19 emerged in the form of case reports and uncontrolled case series as detailed in Table 2 . 3, [25] [26] [27] [28] [29] All patients in these reports received remdesivir through compassionate use or expanded access programs. 14, 30 The largest report included 61 patients from centers in North America, Europe and Japan. 3 All patients were hospitalized with microbiologically confirmed COVID-19 and had an oxygen saturation ≤ 94% on room air or required oxygen support. Those with severe renal impairment, elevated hepatic enzymes, or receiving another investigational agent at baseline were excluded. Of the 53 patients with short-term follow-up data available, 30 (56%) were receiving mechanical ventilation at baseline and a further 4 (8%) required extracorporeal membrane oxygenation (ECMO). Remdesivir was started at a median of 12 days following symptom onset. After a median follow-up of 18 days, 7 (13%) patients died including 6 (18%) who were receiving invasive ventilation. Adverse events were reported in 32 (60%) patients, including 12 (23%) who experienced at least one serious adverse event. The most frequent adverse events were hepatic enzyme elevations, diarrhea, rash, renal impairment, and hypotension.

The publication of this report generated a great deal of controversy. The authors rightly acknowledge many of its limitations including the small sample size, the short duration of follow-up, missing data and the absence of a control group. 3 The lack of post day 1 data on 7 patients is particularly concerning and not adequately addressed in the publication. In addition, a target sample size was not reported nor was a rationale given for why the data were analyzed and reported at the point they

were. It is unclear how many physicians applied for compassionate use for their patients but were denied. It would be interesting to know how these patients differed from the small number whose request for remdesivir was approved. Finally, preclinical studies suggest that remdesivir has little benefit when administered after the peak in viral replication has occurred. 7-9, 14, 19 Although the precise timing of peak viral loads was not accessed in these patients, it may be problematic to attribute favorable outcomes to the remdesivir when initiation was delayed beyond 12 days for many patients.

Against this backdrop, the first randomized, double-blind, placebo-controlled study evaluating remdesivir for COVID-19 was recently published. 31 In this study 237 hospitalized adults with severe COVID-19 were enrolled at 10 centers in Wuhan, Hubei, China and randomized (2:1) to remdesivir or matching placebo for a planned 10-day treatment course (200mg IV day 1, 100mg IV daily on days 2 to 10). Severe COVID-19 was defined as a SARS-CoV-2 positive respiratory specimen by RT-PCR, pneumonia confirmed by chest imaging and an oxygen saturation ≤ 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤ 300mmHg. The primary outcome was time to clinical improvement defined as discharge alive from hospital or a 2-point improvement on a 6-point ordinal scale adapted from the World Health Organization's 8-point illness severity scale. 32 The study was stopped before reaching its target sample size of 453 due to slow enrollment.

Baseline characteristics were similar between groups: the median duration of illness before enrollment was 10 days and most patients (82%) required only low-flow supplemental oxygen at baseline. 31 Use of antibiotics (91%) and corticosteroids (66%) were high in both groups. In addition, 28% and 32% of patients received lopinavir/ritonavir and/or interferon-α2β, respectively during the course of their illness. With regards to the primary outcome, there was no significant difference in time to clinical improvement between the remdesivir and placebo groups [ 

This article is protected by copyright. All rights reserved adequately powered clinical trials or meta-analyses. Considering remdesivir's potent in vitro activity against SARS-CoV-2 and impressive results in pre-clinical models, one of the most unexpected findings in this study was that remdesivir had no impact on viral load. It is plausible that the delayed time to administration may have played a role. On the other hand, in vitro activity and animal data often do not translate into meaningful benefit for patients. 5, 33, 34 Strengths of this study include its randomized, double-blind, placebo-controlled design, high protocol adherence and low loss to follow-up. 31 Premature termination however leaves an underpowered study with inconclusive results. Although cautious of over-interpretation, the point estimate for the primary outcome (HR 1.23) suggests any benefit of remdesivir may be more modest than hoped for (HR 1.40) and the small difference in favor of remdesivir for the composite primary outcome appeared to be driven largely by change in oxygenation status rather than the more clinically meaningful hospital discharge. As discussed in the safety section, this study did give valuable data to help better characterize the adverse effect profile of remdesivir.

On the same day that the peer-reviewed publication of the study by Wang and colleagues was released, partial results of the National Institute of Allergy and Infectious Diseases sponsored Adaptive COVID-19 trial (ACTT-1) were made public in a press release. 31 ACTT-1 was a randomized, double-blind, placebo-control study evaluating remdesivir (200mg IV day 1, then 100mg IV days 2 to 10) in hospitalized adult patients with COVID-19. The primary endpoint, (which was changed 9 days before the independent data safety monitoring board meet to review the results announced in the press release) was time to recovery within 28 days after randomization using a 3point ordinal scale. After 606 recovery events, the median time to recovery was 11 days in the remdesivir group vs. 15 days in the placebo group (HR 1.31; 95% CI 1.12 to 1.54). Mortality was numerically, but not statistically lower, in the remdesivir group (8.0% vs. 11.6%; p = 0.059). 31 In a second statement, Gilead announced that similar outcomes had been demonstrated in their open-label, multicenter clinical trial of 5 vs. 10 days of remdesivir in patients with COVID-19 not requiring invasive mechanical ventilation or ECMO. 35 More comprehensive data about these studies is anticipated. As of 5 May 2020, there are 10 clinical studies underway and registered on clinicaltrials.gov, including 6 randomized-controlled trials, the full results of which are eagerly awaited. 36 (Table 3) 

This article is protected by copyright. All rights reserved Information on the safety profile of remdesivir is rapidly evolving. Until recently, most clinical experience has been in patients with Ebola virus infection which has very different clinical manifestations compared to COVID-19 making extrapolation of drug safety across populations problematic. 5, 14 In the PALM study, 9 of 175 patients who received remdesivir for Ebola virus infection experienced serious adverse events judged by trial investigators to be potentially related to remdesivir. 5 The most serious of these was hypotension during the loading dose rapidly followed by cardiac arrest and death. 5 Among 38 Ebola virus infection survivors who were enrolled in the single arm phase II PREVAIL IV study, 1 patient required a remdesivir dose reduction due to transaminase elevations. 14 Safety data from four phase 1 PK studies in healthy volunteers has also been partly reported. 3, 23 In these studies, subjects received single remdesivir doses of up to 225mg or multiple doses of 150mg once daily for 7 or 14 days or 200mg once followed by 100mg daily for a total of 5 or 10 days. The most common adverse events, recorded in at least 5 subjects, were phlebitis, constipation, headache, ecchymosis, nausea and extremity pain. 3 Transient asymptomatic Grade 1 or 2 alanine aminotransferase (ALT) elevations were observed in most subjects (exact frequency not reported) in the multi-dose PK studies including 1 individual with ALT values > 10 x baseline. 3, 23 Transaminase increases have also been reported in COVID-19 patients treated with compassionate use remdesivir (Table 2) 3, 23, 26, 28 In the report detailing the first 12 COVID-19 cases in the US, all 3 patients who received remdesivir experienced transient transaminase elevations and gastrointestinal symptoms. 26 In addition one patient in the case series from France experienced ALT elevation to 3 times the upper limit of normal and a maculopapular rash leading to remdesivir discontinuation 4 days following the first dose. 28 The FDA reports that among 163 patients enrolled in the compassionate use program, the overall incidence of liver function test abnormalities was 11.7%. 23 Seven cases were considered serious. The time to onset from first dose ranged from 1 to 16 days.

With the exception of 1 case of seriously elevated bilirubin, none of the other cases had associated hyperbilirubinemia or symptoms of hepatitis. 23 In the RCT reported by Wang and colleagues, adverse effects were recorded in 66% of patients randomized to remdesivir of which 8% were grade 3 or 4 (thrombocytopenia n =4, hypokalemia n=2, hyperkalemia n = 2, anemia n=1, increased total bilirubin n = 1) . 31 The incidence and distribution of adverse effects was similar in the placebo group. Aspartate aminotransferase (AST) elevations were observed in 5% of patients in the remdesivir arm compared to 12% in the placebo arm. No patients in Accepted Article either arm experienced grade 3 or 4 transaminase elevations. More patients in the remdesivir discontinued treatment prematurely (12% vs. 5%) with respiratory failure or acute respiratory distress syndrome being the most common event leading to drug discontinuation in the remdesivir group. In a summary of safety data reported by the FDA from the a remdesivir clinical trial comparing 5 and 10day treatment courses in patients with COVID-19, Grade 3 and 4 ALT and/or AST elevations occurred in 7% patients. Elevations in bilirubin were uncommon (1.3%). 23 At this time, it is unclear if the liver enzyme abnormalities seen in patients receiving remdesivir for COVID-19 are a component of the infectious process or due to the drug. The fact that abnormalities, albeit less severe, were seen in healthy volunteers suggests remdesivir is at least partly culpable.

Whether asymptomatic abnormalities are harbingers of more serious liver toxicity is also unknown.

Other approved nucleoside analogues including those used to treat HIV, hepatitis B and cytomegalovirus, are known to cause liver injury by a variety of mechanisms. 24 The most common involves inhibition of mitochondrial DNA synthesis leading to mitochondria depletion or dysfunction.

First generation HIV reverse transcriptase inhibitors are thought to cause hepatic injury by this mechanism. Mitochondrial dysfunction can affect multiple tissues manifesting as myopathy, neuropathy, pancreatitis, bone marrow suppression and/or hepatic injury. 24 Extra-hepatic manifestations of mitochondrial dysfunction have not been reported in patients exposed to remdesivir to date. Nucleoside analogues may also cause liver injury through acute hypersensitivity reactions or the production of toxic intermediates. 24 These reactions tend to be idiosyncratic and uncommon whereas transaminase elevations are consistently observed in a minority of remdesivir treated patients. A fulsome safety assessment of remdesivir will require thorough review of data from recently completed and ongoing studies in addition to post-marketing surveillance and real-world experience.

At the time of writing, no in vivo drug interaction studies of remdesivir have been published but the ability of remdesivir to inhibit or induce cytochrome P450 (CYP450) enzymes and transporters has been tested in vitro. 14 Importantly however, as a pro-drug, remdesivir is rapidly degraded in vivo so the potential for clinically significant drug interactions is likely limited. 14 Data on the potential for remdesivir metabolites to perpetrate drug interactions is even scarcer. In in vitro studies, remdesivir was a weak inhibitor of CYP1A2, CYP2C9, CYP2C19 and CYP2D6. 14 Remdesivir's IC 50 for CYP3A was 1.6 μM suggesting inhibition may occur briefly with standard human exposures. Inhibition of Accepted Article CYP450 enzymes by metabolites was not investigated. 14 Tests of remdesivir CYP450 induction have been inconsistent; it may induce CYP1A2 and CYP2B6. 14 Again the clinical importance of this is questionable. GS-441524 and GS-704277 demonstrated no CYP450 induction in these studies.

Remdesivir was found to be a substrate (OATP1B, P-glycoprotein) or inhibitor (OAT1B1, OAT1B3) of several drug transporters. 14 There are no exclusion criteria related to drug-drug interactions in current remdesivir clinical studies (Table 3) .

Remdesivir is available in 2 bioequivalent formulations: a concentrated solution (5mg/mL) and a lyophilized powder formulation. 14, 18 Vials contain 100mg of remdesivir and are preservative-free. 14, 18 Readers are referred to the FDA Fact Sheet for full storage, preparation and administration instructions. 18 For adults and children weighing ≥ 40kg requiring invasive mechanical ventilation or ECMO, the recommended dose is 200mg IV on day 1 followed by 100mg IV once daily on days 2 to 10. For those not requiring invasive mechanical ventilation or ECMO, a 5 day regimen is recommended.

Doses should be administered over 30 minutes to 2 hours. Readers are referred to the FDA Fact Sheet for full pediatric dosing recommendations. 18 There is no information on direct IV push, intramuscular or subcutaneous administration at this time.

At this time there are no therapies that have been scientifically proven to improve mortality in COVID- 19 . Current management is largely focused on supportive care and prevention of complications. 37, 38 Efficacious and safe antiviral agents are therefore urgently needed to relieve the burden on healthcare systems. As detailed in this review, remdesivir is a nucleoside analogue pro-drug with unique structural features that allow high concentrations of the active triphosphate metabolite to be delivered intracellularly. 6 It evades proofreading to successfully inhibit viral RNA synthesis and has demonstrated potent antiviral activity against β-coronaviruses, including SARS-CoV-2 both in vitro and in animal models. 7-12, 15, 19, 20 These data, coupled with early safety data from clinical experience in Ebola virus infection 5 , provide strong rationale for prioritizing testing of remdesivir in COVID-19 clinical trials. The unpredictable nature of a pandemic however poses many challenges to researchers attempting to conduct clinical trials. 39 The first randomized controlled trial evaluating remdesivir for COVID-19 was conducted a multiple sites in the initial outbreak epicenter yet it failed

This article is protected by copyright. All rights reserved to meet its target sample size due to slow enrollment after the surge in cases diminished and it produced inconclusive results. When patient enrollment in clinical trials is not available, many clinicians face intense pressure to offer unproven therapies based on compelling pre-clinical data. As of April 30, 2020, more than 2000 patients with COVID-19 have received remdesivir through compassionate use or expanded access programs. 35 It is impossible to know if these patients benefited or were harmed but we do know these programs do little to advance science. Efforts must focus on ensuring the necessary infrastructure is in place to expand patient access to pragmatic clinical trials and make it simple for clinicians to enroll them. This could obviate the need for compassionate use programs. With at least 6 remdesivir randomized-controlled trials currently underway worldwide, there is reason to be optimistic that we will accumulate good data and learn if remdesivir provides a meaningful benefit to COVID-19 patients.

Infectious Diseases Society of America. April 2020. https://www.idsociety.org/practice- 

This article is protected by copyright. All rights reserved 

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention

Compassionate Use of Remdesivir for Patients with Severe Covid-19

Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options

Controlled Trial of Ebola Virus Disease Therapeutics

Discovery and Synthesis of a Phosphoramidate Prodrug of a

Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses

Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Accepted Article This article is protected by copyright. All rights reserved

Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Evaluation of sulfobutylether-beta-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy

Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope

Pneumonia from human coronavirus in a macaque model

Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2

Delayed Initiation of Remdesivir in a COVID-19 Positive Patient

All rights reserved 26. Team C-I. Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States

COVID-19 in Solid Organ Transplant Recipients: Initial Report from the US Epicenter

Clinical and virological data of the first cases of COVID-19 in Europe: a case series

A Community Transmitted Case of Severe Acute Respiratory Distress Syndrome due to SARS CoV2 in the United States. Clin Infect Dis 2020. 30. Emergency access to remdesivir outside of clinical trials

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

World Health Organization. Covid-19 Therapeutic Trial Synopsis

Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges

Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1

Earnings Results

Clinical Management of Patients with Moderate to Severe COVID-19 -Interim Guidance. Public Health Agency of Canada/Canadian Critical Care Society/Association of Medical Microbiology and Infectious Disease Canada

Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19

Accepted Article