Truseltiq
infigratinib
Sources:FDA multi-discipline review ↗
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
“Toxicology studies in rat and dogs assessed the toxicity of infigratinib after once daily oral administration up to 26 weeks in rats and 39 weeks in dog (high dose of 3 mg/kg/day in both species).”
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
“Toxicology studies in rat and dogs assessed the toxicity of infigratinib after once daily oral administration up to 26 weeks in rats and 39 weeks in dog (high dose of 3 mg/kg/day in both species).”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Study title / number: BGJ398: A 39‐Week Oral Gavage Toxicity Study in Dogs with a 13‐Week Recovery Period / 2821‐002”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“After 26 or 39 weeks of infigratinib administration in rats and dogs, respectively, the main target organ was bone.”
Route in tox
Oral (gavage)
“Oral dosing in animals was consistent with the intended clinical route of administration for infigratinib.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosome aberration and in vivo rat bone marrow micronucleus assays
“Infigratinib was not mutagenic in the bacterial reverse mutation test. Infigratinib was not clastogenic in an in vitro human peripheral blood lymphocyte chromosome aberration assay or an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies are not recommended for the proposed indication.”
Reproductive & developmental
Rat EFD: embryofetal death at 10 mg/kg/day, reduced fetal weight at ≥3 mg/kg/day, fetal abnormalities at all doses
“Increases in embryo‐fetal death, with corresponding reductions in the numbers of viable fetuses, were observed at 10 mg/kg/day, and reductions in mean fetal body weights were observed at 3 and 10 mg/kg/day. Fetal abnormalities were observed at increased incidences at all doses.”
Safety pharmacology
No significant cardiovascular effects in telemetered dogs; no neurobehavioral or respiratory effects in rats
“Infigratinib had no toxicologically significant effects on cardiovascular function in telemetered dogs or on neurobehavioral and respiratory functions in rats.”
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 Truseltiq 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: Bone (reduced strength and density, growth plate fractures) and liver (centrilobular vacuolation, mild focal necrosis in rat) (FDA multi-discipline review, p. 43)
NOAEL / key findings
Bone (reduced strength and density, growth plate fractures) and liver (centrilobular vacuolation, mild focal necrosis in rat)
“Targets of toxicity included bone (decreases in bone strength, decreases in total bone mineral density, and multifocal growth plate fractures) and liver (centrilobular vacuolation and mild focal necrosis in the rat).”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Extensive tissue distribution including brain; specific uptake into melanin-containing structures in pigmented rats
“[14C]‐infigratinib was extensively distributed into peripheral tissues in rats after oral and IV doses, including brain, and was specifically taken up into melanin‐containing structures in pigmented rats.”
Modality-specific risk
FGFR-mediated calcium/phosphorus imbalance with ectopic mineralization; corneal, bone, teeth and skin toxicity
“When infigratinib was administered to rats and/or dogs for ≤13 weeks the important toxicities included changes in calcium/phosphorus homeostasis, ectopic tissue mineralization in multiple tissues, changes in the cornea, bone, epithelial tissues, teeth, and/or hair/skin.”