Egaten
triclabendazole
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not stated Not stated
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“TCBZ was administered as a diet admixture to rats and beagle dogs at doses of 10, 100 and 1000 ppm daily, for 13 weeks.”
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
“TCBZ was administered as a diet admixture to rats and beagle dogs at doses of 10, 100 and 1000 ppm daily, for 13 weeks.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“TCBZ was administered as a diet admixture to rats and beagle dogs at doses of 10, 100 and 1000 ppm daily, for 13 weeks.”
Pivotal GLP studies
13-week rat and 13-week beagle dog dietary studies
“TCBZ was administered as a diet admixture to rats and beagle dogs at doses of 10, 100 and 1000 ppm daily, for 13 weeks.”
Route in tox
Oral (dietary admixture)
“Route of administration: Orally via diet”
Skipped studiesopen answer page →
Genotoxicity
Negative in a 6-assay battery including Ames, chromosome aberration and micronucleus assays
“No genotoxic potential was noted for triclabendazole tested in a battery of 6 genotoxicity in vitro and in vivo assays which include a bacterial reverse mutation assay, chromosome aberration assays, and a micronucleus assay.”
Carcinogenicity
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.
Reproductive & developmental
No fertility effects in rats; not embryotoxic in rat and rabbit EFD studies up to 200 and 20 mg/kg/day
“Orally administered TCBZ did not have effects on fertility in rats. Oral administration of TCBZ was not embryotoxic in rats and rabbits up to 200 and 20 mg/kg/day, which is 1.6 and 0.3 times the clinical dose respectively, based on a body surface area comparison.”
Safety pharmacology
No stand-alone hERG assay; GLP dog cardiovascular study showed transient QTc prolongation at 100 mg/kg
“A GLP-compliant single-dose cardiovascular study in dogs indicated transient QTc interval prolongation in dogs after dosing with TCBZ at 100 mg/kg which is about 2.5 times the proposed clinical dose based on body surface area comparison.”
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 Egaten 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: NOAEL 0.7-0.8 mg/kg/day in rats and 0.35 mg/kg/day in dogs (10 ppm diet) (FDA multi-discipline review, p. 38)
NOAEL / key findings
NOAEL 0.7-0.8 mg/kg/day in rats and 0.35 mg/kg/day in dogs (10 ppm diet)
“The no observed adverse effect level (NOAEL) was 0.7 to 0.8 mg/kg/day dose in rats (10 ppm) and 0.35 mg/kg/day dose in dogs (10 ppm).”
Risksopen answer page →
Immune & cytokine safety
Guinea pig sensitization: no reaction after epidermal challenge; contact dermatitis unlikely
“No difference between the test and the control group was seen after epidermal challenge application, which suggests that the drug may not produce contact dermatitis.”
Biodistribution & persistence
Extensive distribution in rats; slight accumulation after repeat dosing, 2-fold (thyroid, skin) to 6-fold (brain)
“Drug distribution was extensive in rats with only a slight accumulation in most organs and tissues investigated after 10 daily oral doses of 1 mg/kg. The accumulation of radioactivity was between 2-fold (thyroid and skin) and 6-fold (brain)”
Modality-specific risk
QT prolongation in dogs, likely mediated by the sulfone metabolite
“QTc interval effects in the dog correlated with peak sulfone metabolite concentrations and hence, it is likely that the sulfone metabolite may be playing a role in the observed QTc interval prolongation.”