Inrebic
fedratinib
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
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
“In the rat study, fedratinib was administered at 0, 3, 10, or 30 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
Pivotal GLP studies
6-month rat and 9-month dog repeat-dose studies
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
Route in tox
Oral gavage
“A 9‐Month Toxicity Study of TG101348 Administered by Oral Gavage to Dogs”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosomal aberration and rat micronucleus assays
“Fedratinib was not mutagenic in a bacterial reverse mutation (Ames) assay, or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or in vivo in a micronucleus test in rats.”
Carcinogenicity
6-month Tg.rasH2 mouse: no drug-related neoplasms; no 2-year rat study
“In a 6-month carcinogenicity study in transgenic Tg.RasH2 mice, there were no neoplasms that were attributed to treatment with fedratinib. No 2-year carcinogenicity study in rats was performed.”
Reproductive & developmental
Rat fertility: no remarkable effects; rat EFD: maternal toxicity at mid and high doses
“There were no remarkable fedratinib‐related effects in the FEED study. In the EFD study in rats, fedratinib was maternally toxic at the middle and high dose levels with lower gestational body weight gain and decreased gravid uterine weights.”
Safety pharmacology
No significant cardiovascular or respiratory effects in dogs; no clear CNS effects in rats (non-dose-dependent miosis)
“In vivo, fedratinib was not associated with toxicologically significant effects on cardiovascular or respiratory parameters in dogs. There were no clear drug‐related CNS effects in rats; eye miosis and lack of pupillary responses were observed but were non‐dose‐dependent.”
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 Inrebic 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: Rat targets: bone marrow and liver; also lymphoid tissues, lungs and heart (EMA assessment report, p. 34)
NOAEL / key findings
Rat targets: bone marrow and liver; also lymphoid tissues, lungs and heart
“In rats, the main target organs of toxicity included the bone marrow and liver. Effects were also observed in the lymphoid tissues, lungs and heart.”
Risksopen answer page →
Immune & cytokine safety
Bone marrow hypoplasia and lymphocyte depletion (spleen, thymus, lymph nodes) in all species; immunosuppressive
“In conclusion, fedratinib-related effects on the bone marrow (hypoplasia) and lymphoid tissues (lymphocyte depletion in the spleen, thymus and lymph nodes) in all three species are likely symptoms of exaggerated pharmacology and indicate clear immunosuppressive properties of fedratinib”
Biodistribution & persistence
Whole-body distribution in rats incl. melanin-containing skin and eyes; ocular elimination ~40 days
“Radiolabeled [14C]‐fedratinib was distributed throughout the whole body of the rat, including to the skin and eyes (i.e. melanin‐containing tissues). Elimination from the eyes was approximately 40 days.”
Modality-specific risk
Thiamine transporter (ThTr-1/ThTr-2) inhibition and thiamine levels, assessed in vitro and in rats
“The ability of fedratinib to inhibit human thiamine transporters ThTr‐1 and ThTr‐2 was evaluated using biochemical assays, and to change thiamine levels was assessed in a GLP‐ compliant 28‐day repeat‐dose pharmacodynamic study in rats.”