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.”
Species: general tox
Rat and cynomolgus monkey (up to 1 month); 1-week follow-up studies in cynomolgus and rhesus monkeys
“repeat-dose toxicology studies in rats and Cynomolgus macaques for up to a month; two follow-up 1-week toxicology studies in Cynomolgus and Rhesus macaques”
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“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.”
Species: carcinogenicity
Not conducted (short-term use)
“RDV is indicated for short-term use only, no carcinogenicity studies have been performed. This is agreed upon.”
Surrogate used in
No surrogate used; in vivo studies used remdesivir in a formulation representative of the clinical formulation
“Nonclinical in vivo studies were in general performed with a formulation of remdesivir in 12% (w/v) sulfobutylether B-cyclodextrin sodium (SBECD) in sterile water for injection, pH 3.5 +/-0.1, which is representative of the clinical formulations.”
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”
Genotox: Ames
Negative (remdesivir and GS-441524)
“RDV and metabolite GS-441524 were negative in in vitro Ames tests.”
Genotox: in vitro mammalian
Human lymphocyte chromosome aberration: equivocal with metabolic activation, negative without
“In a chromosome aberration assay in human peripheral blood lymphocytes RDV showed an equivocal response after metabolic activation and was negative without metabolic activation.”
Genotox: in vivo
Rat micronucleus: negative up to 50 mg/kg/day
“In an in vivo micronucleus test performed in rats, RDV was negative up to doses of 50 mg/kg/d at GS-441524 exposures of about an order of magnitude higher than the anticipated human exposure.”
Carcinogenicity model
Not conducted (short-term use)
“RDV is indicated for short-term use only, no carcinogenicity studies have been performed. This is agreed upon.”
Carcinogenicity timing
Not required: short-term use only, no carcinogenicity studies performed
“RDV is indicated for short-term use only, no carcinogenicity studies have been performed. This is agreed upon.”
hERG / QT
Weak hERG inhibition: IC50 28.9 μM, at least 26-fold above free Cmax at 200 mg
“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; at least 6-fold and 26-fold, respectively, above the estimated free drug concentration (1.1 μM) at Cmax of the currently proposed 200-mg maximum clinical dose.”
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.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Hypersensitivity Including Infusion-related and Anaphylactic Reactions
- Increased Risk of Transaminase Elevations
- Risk of Reduced Antiviral Activity When Coadministered with Chloroquine Phosphate or Hydroxychloroquine Sulfate
Hypersensitivity & infusion reactionsHepatotoxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week rat and cynomolgus monkey (IV) studies without a recovery phase
“It is not understood why the applicant did not include a recovery phase in the 4-week studies.”
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.”
DART package
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“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.”
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.”
PPND / ePPND: when
Rat PPND completed before the marketing application; no adverse changes
“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.”
Carcinogenicity
Species: carcinogenicity
Not conducted (short-term use)
“RDV is indicated for short-term use only, no carcinogenicity studies have been performed. This is agreed upon.”
Carcinogenicity model
Not conducted (short-term use)
“RDV is indicated for short-term use only, no carcinogenicity studies have been performed. This is agreed upon.”
Carcinogenicity timing
Not required: short-term use only, no carcinogenicity studies performed
“RDV is indicated for short-term use only, no carcinogenicity studies have been performed. This is agreed upon.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat 4-week NOAEL 0.1–0.2x human AUC (GS-441524); below clinical exposure
“In the rat 4-week study, the AUC exposure margins at NOAEL were 0.1/0.2-fold (males/females) for GS-441524, and 0.2/0.4-fold (males/females) for GS-704277.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Infection challenge: mouse SARS-CoV/MERS-CoV and non-human primate SARS-CoV-2/MERS-CoV models
“In vivo efficacy of RDV was assessed via mouse models of SARS-CoV and MERS-CoV infection and non-human primate models of SARS-CoV-2 and MERS-CoV infection.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: rhesus SARS-CoV-2 study insufficient for definitive conclusions; natural disease course not established
“Unfortunately, the sponsor failed to adequately establish the natural progression of the disease in this animal model. Therefore, results from this study are generally not sufficient to draw any definitive conclusions concerning RDV’s potential to treat COVID-19 in humans.”
Flexibilityopen answer page →
Flexibility accepted
RecoveryQuestioned
No recovery phase in the 4-week rat and monkey toxicity studies
“In the 2-week rat study the effects were mainly reversible, but it is not known whether this is the case after a longer treatment period. It is not understood why the applicant did not include a recovery phase in the 4-week studies.”
Safety marginVerdict not stated
Rat 4-week NOAEL exposures below clinical exposure for the main metabolites
“In the rat 4-week study, the AUC exposure margins at NOAEL were 0.1/0.2-fold (males/females) for GS-441524, and 0.2/0.4-fold (males/females) for GS-704277.”
Efficacy modelQuestioned
Rhesus SARS-CoV-2 efficacy study did not establish the natural disease course
“Unfortunately, the sponsor failed to adequately establish the natural progression of the disease in this animal model. Therefore, results from this study are generally not sufficient to draw any definitive conclusions concerning RDV’s potential to treat COVID-19 in humans.”
DARTQuestioned
Female rat fertility effects attributed by the applicant to maternal stress; argument not accepted
“Taken together, it cannot be agreed that the data are solid enough to conclude that the adverse effects in female rats are consequences of maternal stress and not human relevant as argued by the Applicant.”
Impurity or metaboliteVerdict not stated
No dedicated toxicity studies with remdesivir metabolites beyond a non-GLP Ames test of GS-441524
“The metabolite GS-441524 was tested in a non-GLP reverse mutation assay and concluded as negative. Apart from this in vitro study, no other dedicated studies were performed with remdesivir metabolites.”
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