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.”
Species: general tox
Rat and beagle dog (13-week 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.”
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“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.”
Species: 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.
Surrogate used in
No surrogate used; triclabendazole itself 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.”
Genotox: Ames
Negative, with and without metabolic activation
“In the experiments performed without and with microsomal activation, none of the tested concentrations of the drug led to an increase in point mutations in comparison with the negative control.”
Genotox: in vitro mammalian
CHO cell cytogenetic (clastogenicity) test: negative
“Under the given experimental conditions, no evidence of clastogenic effects was obtained in CHO cells in vitro treated with TCBZ.”
Genotox: in vivo
Micronucleus assay: negative
“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 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.
Carcinogenicity timing
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.
hERG / QT
No stand-alone hERG assay; transient QTc prolongation in dogs at 100 mg/kg single dose (~2.5x clinical dose, BSA)
“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.”
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
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week dietary rat (GLP) and dog (non-GLP) studies; recovery phase not stated
“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.”
DART package
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“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.”
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.”
PPND / ePPND: when
2-generation combined fertility and PPND study in rat completed before the marketing application
“In a 2-generation, combined fertility and pre- and postnatal developmental toxicity study in rats, decreases in body weight gain of second generation pups (F2) were observed at the highest dose”
Carcinogenicity
Species: 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.
Carcinogenicity 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.
Carcinogenicity timing
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.
Safety marginopen answer page →
Safety margin at NOAEL
Rat repeat-dose NOAEL 10 ppm (0.75 mg/kg/day) below the proposed clinical dose (BSA)
“The NOAEL was determined to be 10 ppm (corresponding to a mean of 0.75 mg/kg/day dose) which is below the proposed clinical dose based on a body surface area comparison.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Published studies in animals experimentally infected with F. hepatica or F. gigantica; in vitro fluke motility and tegument assays
“The activity of TCBZ was reported in animals experimentally infected with F. hepatica or F. gigantica”
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
Studies suggest TCBZ and metabolites are active against Fasciola, with activity varying between immature and adult worms
“Overall, the studies suggest that TCBZ and its metabolites are active against Fasciola worms; the activity appears to vary against the immature and adult worms.”
Flexibilityopen answer page →
Flexibility accepted
OtherAcceptedBeyond the letter
Nonclinical package consists of older studies conducted to support the veterinary product
Why: Data from the veterinary studies considered valid to support the clinical formulation · Other reason
“The preclinical investigations with TCBZ were conducted to support the veterinary product for treatment of fluke diseases. However, the data from these studies are considered valid to support the safety of clinical formulation of TCBZ for the treatment of fascioliasis.”
Safety pharmacologyAccepted with a conditionBeyond the letter
No stand-alone hERG assay; most safety pharmacology studies non-GLP; dog QTc prolongation of unclear relevance
Why: Clinical relevance of dog QT prolongation unclear; thorough QT study to be conducted postmarketing
“As part of the Safety Pharmacology assessments, a stand-alone hERG channel inhibition assay was not conducted with TCBZ. However, in a series of other non-GLP Safety Pharmacology studies, no adverse effects were observed”
“In sum, from a Pharmacology/Toxicology perspective, the clinical relevance of the transient QT prolongation seen in the repeat-dose study as well as in the single dose safety Pharmacology study in dogs is unclear, particularly in the absence of cardiac monitoring in the clinical trials, and hence a post-marketing thorough QT study in the clinic will be conducted as recommended by the clinical review team.”
OtherCriticised but acceptedBeyond the letter
Dietary rat repeat-dose study with group-housed animals and no toxicokinetics
“While, overall the repeat-dose study in rats seems adequate, the study design is, to some extent, flawed, as 5 animals per treatment group were housed together in a cage.”
DARTQuestioned
Rat 2-generation study doses too low to assess postnatal toxicity; no toxicokinetics in any reproductive study
“the study are likely inadequate to indicate whether the drug causes postnatal developmental toxicity apart from the observed body weight loss in F2 offspring. No TK analyses were conducted in any of the reproductive toxicology studies in rats or rabbits.”
Safety marginVerdict not stated
Rat repeat-dose NOAEL of 0.75 mg/kg/day is below the proposed clinical dose
“The NOAEL was determined to be 10 ppm (corresponding to a mean of 0.75 mg/kg/day dose) which is below the proposed clinical dose based on a body surface area comparison.”
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