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.”
Species: general tox
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).”
Species: DART
Rat (fertility, teratology) and rabbit (embryo-fetal, alone and with levodopa/carbidopa)
“The NOAEL is 160 mg/kg/d for this rat fertility study. A rabbit embryo-fetal study was conducted in combination with levodopa/carbidopa.”
Species: carcinogenicity
Mouse and rat (lifetime oral studies)
“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).”
Surrogate used in
No surrogate used; istradefylline tested directly in mouse, rat and dog
“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.”
Genotox: Ames
Negative in 4 Ames 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.”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster lung cells: negative; mouse lymphoma not done (precipitation)
“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.”
Genotox: in vivo
Mouse micronucleus and rat UDS: negative
“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 model
2-year mouse (up to 250 mg/kg/day) and 2-year rat; no tumor increase
“The 2 year mouse carcinogenicity study appears to have been adequately conducted and assessed but the doses do not appear to have been significantly high enough to elicit even a minor level of toxicity at the highest dose of 250 mg/kg/d.”
Carcinogenicity timing
2-year mouse and 2-year rat completed before the marketing application
“The Exec CAC concluded that the 2-year carcinogenicity studies in mouse and rat were adequate and negative, pending confirmation of the sponsor’s statistical analysis by the Agency.”
hERG / QT
No hERG (IKr) inhibition up to 2 µmol/L; no QT effect in telemetered dogs
“The in vitro hERG assay showed no inhibition of the Ikr current at doses up to 2 µmol/L. No significant treatment-related effects were reported in cardiovascular safety studies in telemeterized conscious dogs.”
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.”
Anti-drug antibodies: animals
Guinea pig antigenicity study: no anaphylaxis (ASA/PCA) and no drug-specific antibodies
“Neither ASA nor PCA reactions were found and no specific antibodies to KW-6002 were detected.”
Anti-drug antibodies: patients
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.
Label warnings
- Dyskinesia
- Hallucinations / Psychotic Behavior
- Impulse Control / Compulsive Behaviors
Skin reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
Repeat-dose tox before first-in-human
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.
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week dog (oral) with 12-week recovery
“KW-6002 Toxicity to dogs by repeated oral administration for 52 weeks with a 12-week recovery period”
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”
DART package
Species: DART
Rat (fertility, teratology) and rabbit (embryo-fetal, alone and with levodopa/carbidopa)
“The NOAEL is 160 mg/kg/d for this rat fertility study. A rabbit embryo-fetal study was conducted in combination with levodopa/carbidopa.”
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.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“Therefore, it seems evident that KW-6002 treatment of dams had an effect on viability and body weights of rat pups whether due to prenatal or lactational exposure.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (lifetime oral studies)
“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).”
Carcinogenicity model
2-year mouse (up to 250 mg/kg/day) and 2-year rat; no tumor increase
“The 2 year mouse carcinogenicity study appears to have been adequately conducted and assessed but the doses do not appear to have been significantly high enough to elicit even a minor level of toxicity at the highest dose of 250 mg/kg/d.”
Carcinogenicity timing
2-year mouse and 2-year rat completed before the marketing application
“The Exec CAC concluded that the 2-year carcinogenicity studies in mouse and rat were adequate and negative, pending confirmation of the sponsor’s statistical analysis by the Agency.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 52-week NOAEL (10 mg/kg/d) AUC ~1.4x human exposure at 20 mg/day
“Comparison of Mean Human AUC Data at 20 and 40 mg/day vs Animal Data at NOAEL Levels Dose Human Day 14 20 mg Human Day 14 40 mg Rat 13 week study 80 mg/kg/d Rat 104 week study 320 mg/kg/d Dog 26 week study 16 mg/kg/d Dog 52 week study 10 mg/kg/d Mouse 13 week study 60 mg/kg/d 4405.6 ng.h/mL 7924.6 ng.h/mL 508 ng.h/mL 59706 ng.h/mL 6005 ng.h/mL 6420 ng.h/mL 48389 ng.h/mL Ratio Animal: Human (20 mg dose) 0.11:1 13.5:1 1.36:1 1.4:1 11:1”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
MPTP mouse and primate Parkinson's models, 6-OHDA-lesioned rat, haloperidol catalepsy
“Istradefylline potentiated apomorphine’s effects in a 6-OHDA-lesioned rat model of Parkinson’s disease. In the MPTP-treated primate model of Parkinson’s disease, the symptoms improved and no increase in dyskinesias was found.”
Why that model
Clinical compound has similar high A2A affinity across species (human, marmoset, rat, mouse), allowing direct testing
“Istradefylline showed similar high affinity for the A2A receptor with Ki values of 12.4 nmol/L in human, 11 nmol/L in marmosets, 8.18 nmol/L in rats but higher affinity in the mouse (Ki of 2.2 nmol/L) and lower affinity in the dog (Ki of 65 nmol/L).”
Reviewer's view of the efficacy data
FDA reviewer concluded the drug was active in the MPTP mouse model (improved motor function); nonclinically approvable
“The drug was active in the MPTP-treated mouse model shown by improvement of motor function.”
Flexibilityopen answer page →
Flexibility accepted
OtherCriticised but acceptedBeyond the letter
Brain not adequately evaluated in pivotal dog toxicity studies despite rat brain mineralization; nonclinical deficiency in first-cycle Not Approvable letter
Why: Re-analysis of brain sections from the 26- and 52-week dog studies provided · Weight of evidence
“The nonclinical deficiency was an inadequate evaluation of brain in the pivotal toxicity studies in dog, a concern raised by the finding of brain mineralization in rat.”
“The sponsor has adequately addressed the nonclinical deficiency included in the division’s February 25, 2008, letter by providing a reanalysis of brain sections from the 26- and 52-week toxicity studies in dog.”
GenotoxicityVerdict not stated
No valid mouse lymphoma assay: no compatible solvent, sufficiently high concentrations could not be tested
“The testing laboratory concluded that the mouse lymphoma assay was not appropriate for this compound as sufficiently high doses were not able to be tested.”
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