L-Alanine, N-[(S)-hydroxyphenoxyphosphinyl]-, 2-ethylbutyl ester, 6-ester with 2-C-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-anhydro-D-altrononitrile

602.6

602.22539909

3QKI37EEHE

C152185

|Danger|H372 (50%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]|P260, P264, P270, P314, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Data regarding overdoses of remdesivir are not readily available. Overdoses of other nucleoside analogs like acyclovir can be managed with symptomatic and supportive treatment.

In human volunteer studies, remdesivir therapy given for 7 to 14 days was associated with minor serum aminotransferase elevations (less than 5 times ULN) but without other evidence of hepatic injury. In controlled trials of remdesivir in patients hospitalized with COVID-19, rates of serum ALT elevations were similar or lower in patients receiving remdesivir than in those on placebo. Nevertheless, in most uncontrolled studies and case series, between 10% and 50% of patients treated with remdesivir developed transient, mild-to-moderate serum ALT and AST elevations within 1 to 5 days of starting therapy without changes in serum bilirubin or alkaline phosphatase levels. Elevations above 5 times ULN were reported in up to 9% of patients in several clinical trials, but the abnormalities resolved with discontinuation and were not associated with clinically apparent injury. With more widespread use of remdesivir for COVID-19, rare instances of marked ALT elevations with jaundice have been reported, but largely in patients who were critically ill with multi-organ failure or sepsis, or who had received other potentially hepatotoxic agents such as intravenous amiodarone (Case 2). Confounding the issue is that serum aminotransferase elevations are common during symptomatic SARS-CoV-2 infection (Case 1), present in up to 60% of patients and being more frequent in patients with severe disease and in those with the known risk factors for COVID-19 severity such as male sex, older age, higher body mass index and diabetes. Thus, serum aminotransferase elevations are common during remdesivir therapy but are generally asymptomatic, fully reversible and not associated with jaundice. With more widespread use of this antiviral in patients without severe or critical illness and with longer courses of therapy, features of hepatotoxicity may become more evident.

Remdesivir is 88-93.6% bound to human plasma proteins while its metabolites [GS-441524] and GS-704277 are 2% and 1% bound, respectively.

Remdesivir is indicated for the treatment of adult and pediatric patients aged 12 years and over weighing at least 40 kg for coronavirus disease 2019 (COVID-19) infection requiring hospitalization. Under this indication, remdesivir should only be administered in a hospital or other healthcare setting capable of providing acute care comparable to an inpatient hospital setting. Remdesivir was originally granted FDA Emergency Use Authorization (EUA) on May 1, 2020, for use in adults and children with suspected or confirmed COVID-19 in a hospital setting with an SpO2 ≤94%. Following FDA approval, this EUA was revised to cover hospitalized pediatric patients between 3.5 and 40 kg, as well as those under 12 years of age that weigh at least 3.5 kg, with suspected or laboratory-confirmed COVID-19. Under both the on-label and EUA indications, patients not needing invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) should be treated for 5 days (including the loading dose on day 1) and may be extended up to 10 days if they do not show improvement. Patients requiring invasive mechanical ventilation or ECMO should be treated for 10 days.|Veklury is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen (low- or high-flow oxygen or other non-invasive ventilation at start of treatment).|Treatment of Coronavirus disease 2019 (COVID-19)

Remdesivir is an antiviral nucleotide analogue used for therapy of severe novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) infection. Remdesivir therapy is given intravenously for 5 to 10 days and is frequently accompanied by transient, reversible mild-to-moderate elevations in serum aminotransferase levels but has been only rarely linked to instances of clinically apparent liver injury, its hepatic effects being overshadowed by the systemic effects of COVID-19.

Antiviral Agents

Remdesivir is a nucleoside analog used to inhibit the action of RNA polymerase. The duration of action is moderate, as it is given once daily. Due to much higher selectivity of mammalian DNA and RNA polymerases, including human mitochondrial RNA polymerase, for ATP over remdesivir triphosphate, remdesivir is not a significant inhibitor of these enzymes, which contributes to its overall tolerability and safety profile. Despite this, remdesivir carries risks for hypersensitivity reactions, including anaphylaxis and other infusion-related reactions, elevated transaminase levels, and potential decreased efficacy when combined with [hydroxychloroquine] or [chloroquine].

Drugs that are chemically similar to naturally occurring metabolites, but differ enough to interfere with normal metabolic pathways. (From AMA Drug Evaluations Annual, 1994, p2033) (See all compounds classified as Antimetabolites.)|Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)

Remdesivir is absorbed quickly; maximal plasma concentrations following a single 30-minute intravenous infusion are reached within 0.67-0.68 hours (T_max). Repeated dosing yields a C_max (coefficient of variation as a percent) of 2229 (19.2) ng/mL and an AUC_tau of 1585 (16.6) ng\*h/mL. Remdesivir metabolite [GS-441524] has measured values: T_max 1.51-2.00 hours, C_max 145 (19.3) ng/mL, AUC_tau 2229 (18.4) ng\*h/mL, and C_trough 69.2 (18.2) ng/mL. Another metabolite, GS-704277, has measured values: T_max 0.75 hours, C_max 246 (33.9) ng/mL, AUC_tau 462 (31.4) ng\*h/mL, and an undetermined C_trough. A 10mg/kg intravenous dose given to cynomolgus monkeys distributes to the testes, epididymis, eyes, and brain within 4h.|Remdesivir is 74% eliminated in the urine and 18% eliminated in the feces. 49% of the recovered dose is in the form of the metabolite [GS-441524], and 10% is recovered as the unmetabolized parent compound. A small amount (0.5%) of the [GS-441524] metabolite is found in feces.|Data regarding the volume of distribution of remdesivir is not readily available.|Data regarding the clearance of remdesivir is not readily available.

Remdesivir is a phosphoramidate prodrug that must be metabolized within host cells to its triphosphate metabolite to be therapeutically active. Upon cell entry, remdesivir is presumed to undergo first esterase-mediated hydrolysis to a carboxylate form followed by cyclization to eject the phenoxide moiety and finally hydrolysis of the cyclic anhydride to yield the detectable alanine metabolite (GS-704277). The alanine metabolite is subsequently hydrolyzed to yield the monophosphate form of remdesivir, which is either hydrolyzed again to yield the bare nucleoside metabolite [GS-441524] or phosphorylated by cellular kinases to yield the active triphosphate form.

Remdesivir has an elimination half-life of 1 hour following a single 30-minute intravenous infusion. Under the same conditions, the elimination half-lives of the remdesivir metabolites [GS-441524] and GS-704277 are 27 hours and 1.3 hours, respectively. A 10mg/kg intravenous dose in non-human primates has a plasma half-life of 0.39h. The nucleoside triphosphate metabolite has a half-life of 14h in non-human primates. The nucleoside triphosphate metabolite has a half-life of approximately 20 hours in humans.

COVID-19 is caused by the positive-sense RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of the viral genome is a key step in the infectious cycle of RNA viruses, including those of the _Filoviridae_, _Paramyxoviridae_, _Pneumoviridae_, and _Coronaviridae_ families, and is carried out by viral RNA-dependent RNA polymerase (RdRp) enzymes or enzyme complexes. For both SARS-CoV and SARS-CoV-2, the RdRp comprises nsp7, nsp8, and nsp12 subunits under physiological conditions, although functional RdRp complexes can be reassembled _in vitro_ that incorporate only the nsp8 and nsp12 subunits, similar to the Middle East respiratory syndrome coronavirus (MERS-CoV). Remdesivir is a phosphoramidite prodrug of a 1'-cyano-substituted adenosine nucleotide analogue that competes with ATP for incorporation into newly synthesized viral RNA by the corresponding RdRp complex. Remdesivir enters cells before being cleaved to its monophosphate form through the action of either carboxylesterase 1 or cathepsin A; it is subsequently phosphorylated by undescribed kinases to yield its active triphosphate form remdesivir triphosphate (RDV-TP or GS-443902). RDV-TP is efficiently incorporated by the SARS-CoV-2 RdRp complex, with a 3.65-fold selectivity for RDV-TP over endogenous ATP. Unlike some nucleoside analogues, remdesivir provides a free 3'-hydroxyl group that allows for continued chain elongation. However, modelling and _in vitro_ experiments suggest that at _i_ + 4 (corresponding to the position for the incorporation of the fourth nucleotide following RDV-TP incorporation), the 1'-cyano group of remdesivir sterically clashes with Ser-861 of the RdRp, preventing further enzyme translocation and terminating replication at position _i_ + 3. This mechanism was essentially identical between SARS-CoV, SARS-CoV-2, and MERS-CoV, and genomic comparisons reveal that Ser-861 is conserved across alpha-, beta-, and deltacoronaviruses, suggesting remdesivir may possess broad antiviral activity. Considerations for the use of nucleotide analogues like remdesivir include the possible accumulation of resistance mutations. Excision of analogues through the 3'-5' exonuclease (ExoN) activity of replication complexes, mediated in SARS-CoV by the nsp14 subunit, is of possible concern. Murine hepatitis viruses (MHVs) engineered to lack ExoN activity are approximately 4-fold more susceptible to remdesivir, supporting the proposed mechanism of action. However, the relatively mild benefit of ExoN activity to remdesivir resistance is proposed to involve its delayed chain termination mechanism, whereby additional endogenous nucleotides are incorporated following RDV-TP. In addition, serial passage of MHV in increasing concentrations of the remdesivir parent molecule [GS-441524] led to the development of resistance mutations F476L and V553L, which maintain activity when transferred to SARS-CoV. However, these mutant viruses are less fit than wild-type in both competition assays and _in vivo_ in the absence of selective pressure. To date, no clinical data on SARS-CoV-2 resistance to remdesivir have been described.

2-ethylbutyl (2S)-2-(((2R, 3S, 4R, 5R)-5-(4-aminopyrrolo(2,1-f) (1,2,4)triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy)(phenoxy) phosphoryl) amino) propanoate

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