Tepmetko
tepotinib
Species
RatDog
Longest study
39 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 dog
“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”
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
“Dogs received 3, 10, or 30 mg/kg of tepotinib via oral administration of a hard gelatin capsule every day for 39 weeks, followed by a 12-week recovery period.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”
Pivotal GLP studies
26-week rat and 39-week dog GLP oral studies
“To assess the safety of tepotinib, the Applicant conducted GLP-compliant toxicology studies of up to 26-weeks in Sprague Dawley rats and 39 weeks Marshall Beagle dogs.”
Route in tox
Oral (clinical route); capsules in dogs
“A comprehensive set of non-clinical toxicity studies with tepotinib administered by the oral route (clinical route) in rats, dogs and rabbits have been performed.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro and in vivo micronucleus assays (parent and M506)
“In a standard genotoxicity battery, neither tepotinib nor the major metabolite M506 were positive in either the Ames or the in vitro micronucleus assay regardless of metabolic activation. Tepotinib was also negative in the in vivo micronucleus assay.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Dedicated carcinogenicity studies were not conducted with tepotinib, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
Rabbit EFD: skeletal malformations at doses of 5 mg/kg and above
“At dose levels ≥ 5 mg/kg there was an increased frequency of skeletal abnormalities, including misshapen scapula and clavicle, malpositioned calcaneus and talus, malrotated hind paw, and incomplete ossification of sternebra.”
Safety pharmacology
hERG IC50 1.2 µM (24-fold unbound Cmax); no rat telemetry, dog hemodynamic or ECG effects
“Tepotinib (hydrochloride hydrate) inhibited the Kv11.1 (hERG) channel current with an IC50 of 1.2 µM, at a concentration 24-fold higher than the equivalent unbound maximum plasma concentration of the proposed clinical dose of 500 mg.”
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 Tepmetko 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 oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Liver toxicity in rats and dogs: elevated enzymes, histopathology, liver enlargement (FDA multi-discipline review, p. 40)
NOAEL / key findings
Liver toxicity in rats and dogs: elevated enzymes, histopathology, liver enlargement
“Both species experienced liver toxicity following tepotinib exposure, with dose-dependent elevated liver enzymes (AST, ALT, and/or ALP), histopathologic changes, liver enlargement”
Risksopen answer page →
Immune & cytokine safety
No immunotoxic potential in rat and dog repeat-dose studies
“Data collected from repeat-dose toxicity studies in rats and dogs, including haematology and clinical chemistry investigations, absolute and relative weights and histopathology of lymphoid organs were not indicative for an immunotoxic potential of tepotinib.”
Biodistribution & persistence
Rat QWBA: liver, lungs, kidneys, lymph nodes; eye and skin retention suggesting melanin binding
“In the remaining body, highest concentrations of radioactivity were detected in the liver, lungs, and kidneys and, 24 hours after administration, in the lymph nodes. In pigmented animals, medium levels of radioactivity were found in the eyes and skin throughout the investigational period of 96 hours”
Modality-specific risk
Animal exposures well below clinical exposure, limiting safety margins
“The systemic exposure in the toxicology studies were, overall, considerably lower than observed in humans at clinical dose.”