Lybalvi
olanzapine and samidorphan
Sources:FDA multi-discipline review ↗
Species
RatDog
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
“Toxicity of SAM was evaluated in Sprague-Dawley rats and Beagle dogs up to 6 months and 9 months in duration, respectively.”
Why that species
Dog pharmacokinetics of samidorphan closer to human than rat, including no sex difference in metabolism
“The overall pharmacokinetic profile of SAM in dogs is more closely related to humans than rats, including lack of sex difference in metabolism.”
Surrogate molecule
No surrogate; the clinical compound samidorphan was tested
“Toxicity of SAM was evaluated in Sprague-Dawley rats and Beagle dogs up to 6 months and 9 months in duration, respectively.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog, samidorphan)
“Toxicity of SAM was evaluated in Sprague-Dawley rats and Beagle dogs up to 6 months and 9 months in duration, respectively.”
Pivotal GLP studies
6-month rat and 9-month dog oral samidorphan studies
“Toxicity of orally administered SAM was evaluated in rats and dogs up to 6-months and 9-months in duration, respectively.”
Route in tox
Oral
“Toxicity of orally administered SAM was evaluated in rats and dogs up to 6-months and 9-months in duration, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Samidorphan negative in a standard genotoxicity battery
“SAM was negative in a complete and adequate battery of genetic toxicology assays.”
Carcinogenicity
Samidorphan: up to 95-week rat and 6-month rasH2 mouse studies, no tumors
“SAM is also non-carcinogenic as it did not induce tumors in male and female rats administered SAM for up to 95 weeks at exposures which are approximately 32 and 237 times the MRHD based on AUC, respectively and did not induce tumors in rasH2 transgenic mice administered SAM for 6-months.”
Reproductive & developmental
Samidorphan rat EFD: reduced fetal weight, skeletal variations, slight malformation increase at maternally toxic doses >248x MRHD
“SAM administration to pregnant rats during the period of organogenesis resulted in decreased fetal weights, increased skeletal variations, and a slight increase in total malformations at doses that were maternally toxic and greater than 248 times the MRHD based on AUC.”
Safety pharmacology
Samidorphan and RDC-9986 not significant hERG blockers; no cardiovascular or respiratory effects in dogs at 20x MRHD
“In safety pharmacology studies, SAM and metabolite RDC-9986 were not significant hERG channel blockers, and SAM did not have any significant adverse effects on cardiovascular or respiratory parameters in dogs at doses which are 20 times the maximum recommended human dose (MRHD) of 10 mg SAM based on AUC.”
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 Lybalvi 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: Samidorphan dog NOAEL 1 mg/kg/day, approximately equal to clinical exposure at the MRHD (FDA multi-discipline review, p. 320)
NOAEL / key findings
Samidorphan dog NOAEL 1 mg/kg/day, approximately equal to clinical exposure at the MRHD
“The NOAEL for SAM in dogs is 1 mg/kg/day, which is approximately equal to the clinical exposure at the MRHD of 10 mg SAM based on AUC.”
Risksopen answer page →
Immune & cytokine safety
Non-adverse, partially reversible thymus weight decrease with lymphoid depletion in male dogs
“Non-adverse, partially reversible decreases in thymus weights with corresponding microscopic findings of lymphoid depletion were observed in males only after treatment with OLZ, SAM, and the combination.”
Biodistribution & persistence
Samidorphan highly distributed to tissues; binds melanin-containing tissues including skin and eyes
“SAM is highly distributed to tissues in rats and was found to bind to melanin-containing tissues including skin and eyes and is mainly excreted in urine in rats and dogs.”
Modality-specific risk
Major human metabolite RDC-9986 acts as a partial opioid agonist in vivo
“In vivo rodent behavioral assays demonstrated that RDC-9986 functions as a partial opioid agonist.”