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.
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 absorbed quickly; maximal plasma concentrations following a single 30-minute intravenous infusion are reached within 0.67-0.68 hours (T<sub>max</sub>). Repeated dosing yields a C<sub>max</sub> (coefficient of variation as a percent) of 2229 (19.2) ng/mL and an AUC<sub>tau</sub> of 1585 (16.6) ng\*h/mL. Remdesivir metabolite [GS-441524] has measured values: T<sub>max</sub> 1.51-2.00 hours, C<sub>max</sub> 145 (19.3) ng/mL, AUC<sub>tau</sub> 2229 (18.4) ng\*h/mL, and C<sub>trough</sub> 69.2 (18.2) ng/mL. Another metabolite, GS-704277, has measured values: T<sub>max</sub> 0.75 hours, C<sub>max</sub> 246 (33.9) ng/mL, AUC<sub>tau</sub> 462 (31.4) ng\*h/mL, and an undetermined C<sub>trough</sub>. 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.
