Caplyta
lumateperone
Species
RatMouseDog
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 (mouse up to 3 months)
“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”
Why that species
No species matched human metabolism (monkey, hamster, guinea pig, minipig tested); rat and dog used
“The Applicant was unable to identify an alternative nonclinical species with a similar metabolic profile to humans and, therefore, the rat and dog were used.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the rat 6-month chronic toxicology study, adverse effects occurred at doses of lumateperone that are ~ 5 times the MRHD of 42 mg on a mg/m2 basis.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”
Pivotal GLP studies
6-month rat and 9-month dog oral studies; 3-month mouse
“The toxicological profile of lumateperone was studied in mice, rats, and dogs following oral administration for up to 3, 6, and 9 months, respectively.”
Route in tox
Oral (capsules in dog)
“Route of administration: Oral Capsules”
Skipped studiesopen answer page →
Genotoxicity
Ames and mouse lymphoma positive only with metabolic activation; negative rat micronucleus and Comet
“Lumateperone was positive for mutagenic potential in the Ames test in the presence of metabolic activation in the TA1537 tester strain and the mouse lymphoma test. Lumateperone was negative for clastogenic activity in the in vivo micronucleus assay in rats and was not genotoxic in the in vivo Comet assay in rats”
Carcinogenicity
Lifetime rat and mouse studies: no carcinogenic potential
“Lifetime carcinogenicity studies were conducted in rats and mice, and results showed no carcinogenic potential in either species.”
Reproductive & developmental
Impaired male and female rat fertility and estrus irregularities at ~MRHD
“Oral administration of lumateperone to male and female rats adversely affected male and female fertility and caused estrus cycle irregularities at doses approximately equal to the MRHD of 42 mg lumateperone on a mg/m2 basis.”
Safety pharmacology
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Caplyta 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: Dog CNS adverse effects at 4x MRHD; NOAEL 2x MRHD (mg/m2 basis) (FDA multi-discipline review, p. 41)
NOAEL / key findings
Dog CNS adverse effects at 4x MRHD; NOAEL 2x MRHD (mg/m2 basis)
“Adverse effects in the central nervous system of dogs occurred at doses of lumateperone that are 4 times the MRHD of 42 mg on a mg/m2 basis. The dose of lumateperone that corresponds to the NOAEL was 2 times the MRHD of 42 mg on a mg/m2 basis.”
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
Prolonged uveal tract/retina retention (up to 840 h), suggesting melanin binding
“Notably the uveal tract/retina contained 64% and 42% of peak concentrations of radioactivity 336 hr and 840 hr post-dose, respectively, indicating lumateperone-related material may bind to melanin.”
Modality-specific risk
Systemic intracytoplasmic pigment accumulation with little to no exposure margin
“Oral administration of lumateperone caused systemic intracytoplasmic accumulation of pigmented material in dogs, rats, and mice, with little to no exposure margin relative to the 42-mg MRHD on both a mg/m2 and AUC plasma exposure basis.”