Mechanism of Action
Remdesivir is an adenosine nucleotide prodrug that distributes into cells where it is metabolized to form the pharmacologically active nucleoside triphosphate metabolite. Metabolism of remdesivir to remdesivir triphosphate has been demonstrated in multiple cell types. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA. Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases with low potential for mitochondrial toxicity.
The pharmacokinetics (PK) of remdesivir have been evaluated in adults in several Phase 1 trials.
- Following single-dose, 2-hour IV administration of remdesivir solution formulation at doses ranging from 3 to 225 mg, remdesivir exhibited a linear PK profile.
- Following single-dose, 2-hour IV administration of remdesivir at doses of 75 and 150 mg, both the lyophilized and solution formulations provided comparable PK parameters (AUCinf, AUClast, and Cmax), indicating similar formulation performance.
- Remdesivir 75 mg lyophilized formulation administered IV over 30 minutes provided similar peripheral blood mononuclear cell (PBMC) exposure of the active triphosphate metabolite GS-443902 as remdesivir 150 mg lyophilized formulation administered IV over 2 hours.
- Following a single 150 mg intravenous dose of [14C]-remdesivir, mean total recovery of the dose was greater than 92%, consisting of approximately 74% and 18% recovered in urine and feces, respectively. The majority of remdesivir dose recovered in urine was metabolite GS-441524 (49%), while 10% was recovered as remdesivir.
Sex, Race and Age
Pharmacokinetic differences based on sex, race, and age have not been evaluated.
The pharmacokinetics of remdesivir in pediatric patients has not been evaluated.
Physiologically-based pharmacokinetic models were developed to estimate remdesivir and GS-441524 exposure and predict pediatric patient exposure based on age-dependent physiologic changes (e.g., organ volume/function, blood flow). These simulations do not account for the impact of infection on the pharmacokinetics of remdesivir and GS-441524, which is currently unknown.
Because the excipient SBECD is renally cleared and accumulates in patients with decreased renal function, administration of drugs formulated with SBECD (such as remdesivir) is not recommended in adult and pediatric patients (>28 days old) with eGFR less than 30 mL per minute or in full-term neonates (≥7 days and ≤28 days old) with serum creatinine clearance ≥1 mg/dL unless the potential benefit outweighs the potential risk.