Azstarys
serdexmethylphenidate and dexmethylphenidate
Species
RatDogRabbit
Longest study
26 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 (28-day); rabbit (6-month juvenile, EFD)
“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”
Why that species
Rabbit chosen by cross-species PK analysis as having the highest SDX exposure relative to humans (minimizing d-MPH exposure)
“In order to use the species with the highest SDX exposure compared to humans in the pivotal embryo-fetal development study and the 6-month juvenile animal study, a cross-species analysis was conducted, and the rabbit was determined to be the most appropriate species.”
Surrogate molecule
No surrogate; the clinical compound (SDX) was tested, with d-MPH as comparator
“In rat and dog single- and repeat-dose toxicology studies of up to 28-day duration of oral SDX with d-MPH as a comparator”
Study lengthopen answer page →
Longest pivotal study
26 (6-month juvenile rabbit)
“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”
Pivotal GLP studies
28-day rat and dog studies and 6-month juvenile rabbit study
“The Division agreed to review 28-day repeat-dose toxicology data in two species, an embryo-fetal development study in the rabbit, and 6- month juvenile rabbit study to support this position.”
Route in tox
Oral (gavage / stomach tube)
“A 6-Month Study of KP415 Administered by Oral (Stomach Tube) Administration in Juvenile Rabbits with a 1-Month Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus, in vivo rat bone marrow micronucleus and rat comet assays
“Serdexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mammalian cell micronucleus assay using human peripheral blood lymphocytes, in the in vivo rat bone barrow micronucleus assay, or in the in vivo rat alkaline comet assay.”
Carcinogenicity
Not conducted with SDX; relies on referenced d-MPH (Focalin XR) labeling
“Carcinogenicity studies were not conducted with SDX. The Applicant is relying upon the carcinogenicity data in the referenced product labeling.”
Reproductive & developmental
Rabbit EFD: no maternal or fetal developmental toxicity up to 49x MRHD (400 mg/kg)
“In the embryo-fetal development study in rabbits, there were no findings of maternal or fetal development toxicity at exposures up to 49 times (400 mg/kg) the MRHD.”
Safety pharmacology
CNS, hERG, cardiovascular and respiratory battery: stimulant-type effects comparable to d-MPH; hERG IC50 >25 uM
“All findings for SDX were typical of a CNS stimulant (including dilated pupil, increased activity, increased heart rate and blood pressure, and increased respiratory rate) and all findings were generally comparable for SDX and a comparative dose of d-MPH. In the hERG assay, the IC50 for SDX was considered >25 µM.”
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 Azstarys 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: Dose-limiting stimulant clinical signs and body weight effects; rat NOAEL 25 mg/kg; dog NOAEL below lowest dose (FDA multi-discipline review, p. 45)
NOAEL / key findings
Dose-limiting stimulant clinical signs and body weight effects; rat NOAEL 25 mg/kg; dog NOAEL below lowest dose
“For rats, the exposures at the no adverse effect level (NOAEL) for stimulant-related findings (25 mg/kg) was less than the human exposure at the MRHD. For dogs, the NOAEL for stimulant-related findings was not established because the NOAEL is less than the lowest dose tested.”
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
Wide distribution in rat; highest in eye uvea, kidney, liver, gastric mucosa and small intestine
“[14C]SDX-related radioactivity widely distributed in rat tissues with the highest radioactivity concentrations observed in eye uvea, kidney cortex and medulla, liver, gastric mucosa of stomach, and small intestine.”
Modality-specific risk
New prodrug with longer human half-life and species PK differences: need to exclude SDX-unique toxicity vs d-MPH, chronic/juvenile toxicity
“However, even though SDX is a prodrug of an approved product (d-MPH), we determined that a chronic study adequately assessing SDX toxicity in an appropriate species was needed because SDX is an NME that has a longer half-life in humans (~5.7 hours) compared to other species (~0.5-2 hours).”