Veklury
remdesivir
Species
MonkeyRat
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“Repeat-dose toxicity in rats and cynomolgus monkeys have been conducted, 2-week studies with a 4-week recovery period, and 4-week studies in both species.”
Why that species
Pharmacokinetics: rat and monkey both form the metabolites GS-704277 and GS-441524
“Pharmacokinetic studies supported the selection of the rat and monkey for the assessment of RDV toxicology. Both rat and monkey formed the intermediate metabolite GS-704277 and the nucleoside metabolite GS-441524.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Intravenous administration (slow bolus) of remdesivir to rats at dosage levels of ≥3 mg/kg/day for up to 4 weeks resulted in findings indicative of kidney injury and/or dysfunction.”
Study lengthopen answer page →
Longest pivotal study
4 (4-week rat and monkey)
“Repeat-dose toxicity in rats and cynomolgus monkeys have been conducted, 2-week studies with a 4-week recovery period, and 4-week studies in both species.”
Pivotal GLP studies
2-week (with 4-week recovery) and 4-week GLP studies in rats and cynomolgus monkeys
“Repeat-dose toxicity in rats and cynomolgus monkeys have been conducted, 2-week studies with a 4-week recovery period, and 4-week studies in both species. The 2-week GLP repeat dose studies incorporated a saline and vehicle control group.”
Route in tox
Intravenous
“Intravenous administration (slow bolus) of remdesivir to rats at dosage levels of ≥3 mg/kg/day for up to 4 weeks resulted in findings indicative of kidney injury and/or dysfunction.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, human lymphocyte chromosome aberration and rat micronucleus assays
“Remdesivir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.”
Carcinogenicity
Not conducted (short-term treatment)
“Given the short-term administration of VEKLURY for the treatment of COVID-19, long-term animal studies to evaluate the carcinogenic potential of remdesivir were not conducted.”
Reproductive & developmental
Rat: fewer corpora lutea, implantations and viable embryos at systemically toxic 10 mg/kg; no adverse EFD (rat, rabbit) or PPND effects
“In the reproductive and development toxicity studies, there was a decrease in corpora lutea, a consequent decrease in implantation sites and viable embryos, and lower ovary and uterus/cervix/oviduct weights in the rats at 10 mg/kg; these changes were observed at a systemically toxic dose. There were no remarkable findings in male rats in the fertility study, no adverse findings in embryo-fetal studies in rats and rabbits, and no adverse changes in the pre- and postnatal study in rats.”
Safety pharmacology
Weak hERG inhibition in vitro (IC20 7.5 µM, IC50 28.9 µM)
“RDV did show only a weak inhibition in vitro of the hERG channel, IC20 and IC50 values for the inhibitory effect were 7.5 μM and 28.9 μM, respectively”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Veklury don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Kidney injury in rats at ≥3 mg/kg/day; 4-week rat NOAEL 3 mg/kg/day (0.2–0.4x human GS-441524 AUC) (EMA assessment report, p. 39)
NOAEL / key findings
Kidney injury in rats at ≥3 mg/kg/day; 4-week rat NOAEL 3 mg/kg/day (0.2–0.4x human GS-441524 AUC)
“Also in the 4-week study in rats clinical pathology and microscopic findings indicative of kidney injury and/or dysfunction in animals administered ≥ 3 mg/kg/day, and unscheduled deaths of 2 females and decreased body weight gain and food consumption at 10 mg/kg/day were seen. Based on the nature and severity of the kidney changes the NOAEL was 3 mg/kg/day, which corresponds to 0.4-fold (males) and 0.2-fold (females) the human AUC of GS-441524.”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotoxicity studies; no concerns in repeat-dose studies
“No dedicated immunotoxicity studies have been performed with remdesivir. This is considered acceptable as no concerns were identified by standard assessments in repeat-dose toxicology studies.”
Biodistribution & persistence
Crosses blood-testis barrier; eliminated from most tissues by 96 h; no melanin binding
“Low levels of radioactivity were detected in testes, suggesting [14C]remdesivir-derived radioactivity crossed the blood to testes barrier. Radioactivity was eliminated from majority of the tissues by 96 hours postdose in both SD and LE rats. No melanin binding was observed.”
Modality-specific risk
Nephrotoxicity (kidney tubular epithelium) after short treatment at or below clinical exposures
“The toxicity to kidney tubular epithelium was observed after short treatment durations and at or below clinically relevant exposures.”