Nourianz
istradefylline
Species
RatDog
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The target organs for istradefylline in rats and dogs are consistent and are the adrenal gland (hypertrophy/hyperplasia) and lung (pneumonitis with septal thickening).”
Why that species
No novel human metabolites relative to rat and dog
“In human studies, MI was the primary metabolite and no novel metabolites were identified when compared to the rat and dog data.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Brain mineralization was not detected in mice administered istradefylline (0, 25, 125, or 250 mg/kg/day) orally for two years or in dogs administered istradefylline (0, 10, 30, or 100 mg/kg/day) orally for 52 weeks.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week dog)
“Dog: Re-analysis of brain sections from the 26- and 52-week studies in dog (26-week: 0, 0 (vehicle), 16, 80, or 400 mg/kg/day; 52-week: 0, 10, 30, or 100 mg/kg/day) did not reveal evidence of brain mineralization”
Pivotal GLP studies
26-week rat and 26- and 52-week dog studies
“in the 26-week toxicity study in Sprague-Dawley rat (0, 3, 6, 30, or 160 mg/kg/day) at the highest dose tested, based on a re-examination of brain sections from these studies.) Brain mineralization was not detected in beagle dog in the 26- or 52-week toxicity studies”
Route in tox
Oral (gavage and capsule)
“Pneumonitis with septal thickening was appreciated after oral dosing (both gavage and capsular administrations) in rats and dogs.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames (4 assays), CHL chromosome aberration, mouse micronucleus and rat UDS assays
“Istradefylline was negative in 4 Ames assays for bacterial mutagenicity, the chromosomal aberration assay in Chinese hamster lung cells, the micronucleus assay in mice or the UDS assay in rats.”
Carcinogenicity
Lifetime oral studies in mouse and rat: no evidence of carcinogenicity
“In lifetime oral carcinogenicity studies, there was no evidence of carcinogenicity in mouse (0, 25, 125, or 250 mg/kg) or rat (0, 30, 100, or 320 mg/kg).”
Reproductive & developmental
Teratogenic, with embryofetal and offspring mortality and growth deficits at clinically relevant exposures, without maternal toxicity
“oral administration of istradefylline during pregnancy resulted in teratogenicity (increased incidences of fetal structural abnormalities, embryofetal and offspring mortality and growth deficits) at clinically relevant exposures and in the absence of maternal toxicity.”
Safety pharmacology
No QT or respiratory effects in telemetered dogs at 1000 mg/kg; no hERG inhibition up to 2 µM
“In a later study, telemeterized dogs were treated for 6 weeks at 1000 mg/kg p.o. daily and no significant effects were reported on the QT interval or respiratory parameters. The in vitro hERG assay showed no inhibition of the Ikr current at concentrations up to 2 µmol/L.”
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 Nourianz 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: Target organs in rat and dog: adrenal (hypertrophy/hyperplasia) and lung (pneumonitis with septal thickening) (FDA pharmacology/toxicology review, p. 29)
NOAEL / key findings
Target organs in rat and dog: adrenal (hypertrophy/hyperplasia) and lung (pneumonitis with septal thickening)
“The target organs for istradefylline in rats and dogs are consistent and are the adrenal gland (hypertrophy/hyperplasia) and lung (pneumonitis with septal thickening).”
Risksopen answer page →
Immune & cytokine safety
No antigenicity: no anaphylaxis (ASA/PCA) reactions or drug-specific antibodies
“Neither ASA nor PCA reactions were found and no specific antibodies to KW-6002 were detected. Under the conditions of this study, no antigenicity was determined with KW-6002.”
Biodistribution & persistence
Placental and milk transfer; radioactivity higher and more persistent in fetuses and neonates than in dams
“In two studies of radiolabeled istradefylline in pregnant or nursing rats, the radioactivity persisted for a longer time and at higher levels in both fetuses and neonates than in dams.”
Modality-specific risk
Brain vascular mineralization in rats; human relevance unclear without a known mechanism
“Overall, the available data demonstrate an increase in incidence and severity of brain mineralization only in rat. However, whether this finding is species-specific or not of relevance to humans is unclear, particularly without an identified mechanism of action.”