Vanrafia
atrasentan
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Rat and dog
“Pivotal chronic toxicology studies were conducted in rats for up to 6 months and dogs for up to 9 months.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Study Title: A 39-Week Repeat-Dose Study of Atrasentan in Dogs”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“General toxicity studies were conducted for durations of up to 26 weeks in rats and 39 weeks in dogs.”
Pivotal GLP studies
26-week rat and 39-week dog studies
“General toxicity studies were conducted for durations of up to 26 weeks in rats and 39 weeks in dogs.”
Route in tox
Oral
“Methods: Animals were dosed by oral administration for 9 months.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo mouse micronucleus assays
“There was no evidence of mutagenicity or clastogenicity for atrasentan in in vitro bacteria reverse mutation and chromosomal aberration assays, or in an in vivo mouse micronucleus study.”
Carcinogenicity
2-year rat: benign uterine stromal polyps in females at 24 times the MRHD
“The carcinogenicity assessment of atrasentan in a 2-year rat study showed uterine stromal polyps in females at exposures 24 times the MRHD.”
Reproductive & developmental
Rat and rabbit EFD: teratogenic at exposures below the MRHD
“In animal reproduction studies, oral administration of atrasentan to pregnant rats and rabbits throughout organogenesis at doses that were below the maximum recommended human dose (MRHD) based on area under the curve (AUC) caused teratogenic effects in rats and rabbits”
Safety pharmacology
Dog telemetry: minimal QTc effect up to 51 times clinical Cmax
“In conscious dogs implanted with telemetry transmitters, atrasentan (≥10 mg/kg) showed minimal effects on heart rate-corrected QT interval at doses up to 51 times the maximal concentration achieved at the MRHD.”
First doseopen answer page →
First-in-human starting dose
First-in-human single-dose study started at 139.5 mg; derivation not described
“Initially, the study was designed as a single dose, dose-escalating study with the starting dose of 139.5 mg.”
NOAEL / key findings
No NOAEL in rat or dog; male rat LOAEL 5 mg/kg/day for testicular degeneration
“In the chronic toxicology studies of atrasentan in the rat and dog, a no-observed-adverse-effect level (NOAEL) was not established. In male rats, the lowest dose tested, i.e., 5 mg/kg/day, was considered to be the lowest-observed-adverse-effect level (LOAEL) because of modest testicular degeneration”
Risksopen answer page →
Immune & cytokine safety
No immunosuppressive effect in 6-month rat and 9-month dog studies
“In addition, the repeat-dose toxicology studies in rats for up to 6 months and in dogs for up to 9 months do not suggest an immunosuppressive effect of atrasentan.”
Biodistribution & persistence
Rat: low levels in testes, eyes, bone marrow and fat; not detected in brain
“Low concentrations were observed in testes, eyes, bone marrow, and fat. Radioactivity was not detected in the brain.”
Modality-specific risk
Embryo-fetal toxicity (teratogenicity), an endothelin receptor antagonist class effect
“These findings are consistent with a class effect of developmental anomalies induced by endothelin receptor antagonists.”