Fruzaqla
fruquintinib
Species
RatDog
Longest study
13 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
“Overall, the toxicity profile determined in rat and dog in the non-GLP studies (4-week studies and 26 or 39-week studies with an intermediate 13-week analysis) appears affected a larger number of target organs than the one observed in GLP pivotal studies (two 13-week studies).”
Why that species
Metabolite profile: dog metabolites mostly represent human; rat has the same metabolites in a different ratio
“The species comparison suggests that metabolites in dog represent mostly the metabolites in human but that the rat also has same metabolites present, although in a different ratio.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 13-week repeat-dose toxicology study in dogs, animals were orally administered fruquintinib at 0, 0.03, 0.06, or 0.12 mg/kg daily with a 4-week recovery period.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog GLP studies)
“Given the indication was in the scope of ICH S9 guideline, the two 13-week GLP compliant studies could be considered as the only pivotal studies in the submitted non-clinical package.”
Pivotal GLP studies
Two 13-week GLP pivotal studies in rat and dog; longer earlier studies were non-GLP
“Overall, the toxicity profile determined in rat and dog in the non-GLP studies (4-week studies and 26 or 39-week studies with an intermediate 13-week analysis) appears affected a larger number of target organs than the one observed in GLP pivotal studies (two 13-week studies).”
Route in tox
Oral
“In a 13-week repeat-dose toxicology study in rats, animals were orally administered fruquintinib at 0, 0.3, 0.6, or 1.2 mg/kg daily with a 4-week recovery period.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosome aberration and in vivo rat micronucleus assays
“Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells. The in vivo bone marrow micronucleus assay in rats was negative.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not performed and are not required for pharmaceuticals intended for the treatment of advanced cancer (ICH S9).”
Reproductive & developmental
Rat EFD: teratogenicity and embryo lethality at exposures below clinical exposure
“In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure (see Data ) .”
Safety pharmacology
No significant cardiovascular or respiratory effects in dogs or neurobehavioral effects in rodents
“Fruquintinib did not have a toxicologically significant effect on cardiovascular or respiratory function in dogs or neurobehavioral function 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 Fruzaqla 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: Target organs: liver, kidney, adrenal gland, thymus, spleen, bone marrow and femur (EMA assessment report, p. 40)
NOAEL / key findings
Target organs: liver, kidney, adrenal gland, thymus, spleen, bone marrow and femur
“The identified target organs of fruquintinib toxicity were liver, kidney, adrenal gland, thymus, spleen, bone marrow (sternum), and femur.”
Risksopen answer page →
Immune & cytokine safety
Immune system (thymus, spleen, lymph nodes) a target organ in dog studies
“The non-GLP dog studies identified liver, kidney, GI-tract, adrenal gland, and immune system (thymus and spleen, and lymph nodes in the 39-week study) as target organs.”
Biodistribution & persistence
Wide distribution; highest in GI tract, bladder, uveal tract and pigmented skin (melanin)
“Following a single oral dose of radiolabeled fruquintinib, wide distribution of fruquintinib was observed with the highest radioactivity observed in the esophagus, large intestine, small intestine, stomach, bladder, uveal tract, and pigmented skin.”
Modality-specific risk
Low exposure margins: 13-week rat and dog NOAEL AUC ratios 0.3 and 0.05
“The safety margins (total AUC ratio) derived from the GLP-compliant 13-week rat and dog study NOAELs are 0.3 and 0.05, respectively.”