Lybalvi
olanzapine and samidorphan
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.”
Species: general tox
Rat (6-month) and dog (9-month), samidorphan
“Toxicity of orally administered SAM was evaluated in rats and dogs up to 6-months and 9-months in duration, respectively.”
Species: DART
Rabbit (EFD, samidorphan) and rat (EFD, olanzapine/samidorphan combination)
“SAM administration to pregnant rabbits during the period of organogenesis resulted in maternal toxicity, but no effects on embryofetal development at doses up to approximately 143 times MRHD based on AUC. The administration of the combination of SAM and OLZ to pregnant rats during the period of organogenesis resulted in similar effects”
Species: carcinogenicity
Rat (up to 95 weeks) and rasH2 transgenic mouse (6-month), samidorphan
“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.”
Surrogate used in
No surrogate used; samidorphan tested directly in rats and dogs
“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.”
Genotox: Ames
Negative (samidorphan)
“No evidence of genotoxicity of samidorphan was found in the in vitro Ames bacterial reverse mutation test, the in vitro chromosome aberration assay in human peripheral blood lymphocytes or in the in vivo mouse bone marrow micronucleus assay.”
Genotox: in vitro mammalian
Chromosome aberration in human peripheral blood lymphocytes: negative (samidorphan)
“No evidence of genotoxicity of samidorphan was found in the in vitro Ames bacterial reverse mutation test, the in vitro chromosome aberration assay in human peripheral blood lymphocytes or in the in vivo mouse bone marrow micronucleus assay.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative (samidorphan)
“No evidence of genotoxicity of samidorphan was found in the in vitro Ames bacterial reverse mutation test, the in vitro chromosome aberration assay in human peripheral blood lymphocytes or in the in vivo mouse bone marrow micronucleus assay.”
Carcinogenicity model
Samidorphan: rat up to 95 weeks and rasH2 transgenic mouse 6-month; no tumors (up to 32x/237x MRHD AUC in rats)
“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.”
Carcinogenicity timing
Samidorphan: rat (up to 95 weeks) and 6-month rasH2 mouse completed before the marketing application
“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.”
hERG / QT
Not significant hERG blockers: samidorphan IC50 28.19 µM, RDC-9986 >280 µM
“In safety pharmacology studies, SAM and metabolite RDC-9986 were not significant hERG channel blockers (IC50 values of 28.19 and >280 µM, respectively).”
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.”
Anti-drug antibodies: animals
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.
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
Boxed warning: Increased mortality in elderly patients with dementia-related psychosis
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis
- Precipitation of Severe Opioid Withdrawal in Patients Who Are Physiologically Dependent on Opioids
- Vulnerability to Life-Threatening Opioid Overdose
- Neuroleptic Malignant Syndrome
- Drug Reaction with Eosinophilia and Systemic Symptoms
- Metabolic Changes
- Tardive Dyskinesia
- Orthostatic Hypotension and Syncope
- Falls
- Leukopenia, Neutropenia, and Agranulocytosis
- Dysphagia
- Seizures
- Potential for Cognitive and Motor Impairment
- Body Temperature Dysregulation
- Anticholinergic (Antimuscarinic) Effects
- Hyperprolactinemia
- Risks Associated with Combination Treatment with Lithium or Valproate
- Interference with Laboratory Tests for Opioid Detection
CardiovascularSecondary malignancyMetabolic & endocrineSkin reactionsCytopeniasGastrointestinalNeurotoxicity
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) dog, samidorphan (oral), with 4-week recovery
“Both the 13-week and 9-month repeat-dose studies with 4-week recovery periods also evaluated doses of 1, 3, and 10 mg/kg/day.”
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.”
DART package
Species: DART
Rabbit (EFD, samidorphan) and rat (EFD, olanzapine/samidorphan combination)
“SAM administration to pregnant rabbits during the period of organogenesis resulted in maternal toxicity, but no effects on embryofetal development at doses up to approximately 143 times MRHD based on AUC. The administration of the combination of SAM and OLZ to pregnant rats during the period of organogenesis resulted in similar effects”
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.”
PPND / ePPND: when
PPND in rat (samidorphan alone) completed before the marketing application
“In a pre- and postnatal development study, pregnant rats were administered SAM at oral doses of 10, 30, and 100 mg/kg/day from gestation day 6 through lactation day 20.”
Carcinogenicity
Species: carcinogenicity
Rat (up to 95 weeks) and rasH2 transgenic mouse (6-month), samidorphan
“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.”
Carcinogenicity model
Samidorphan: rat up to 95 weeks and rasH2 transgenic mouse 6-month; no tumors (up to 32x/237x MRHD AUC in rats)
“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.”
Carcinogenicity timing
Samidorphan: rat (up to 95 weeks) and 6-month rasH2 mouse completed before the marketing application
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat samidorphan NOAEL 5 mg/kg/day: 0.4x (males) and 5x (females) MRHD AUC
“The no observed adverse effect level (NOAEL) for SAM in rats is 5 mg/kg/day, which is 0.4 and 5 times the MRHD in males and females, respectively based on AUC.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Olanzapine-induced weight gain and adiposity in rats and nonhuman primates mitigated by samidorphan
“SAM was also able to mitigate OLZ-induced metabolic dysfunction, including weight gain and adiposity, in rats and nonhuman primates (NHP), however it did not prevent OLZ-induced liver insulin resistance in rats or have any effects on HbA1c levels or glucose tolerance.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: overall pharmacodynamic effect of olanzapine, samidorphan and major metabolites at clinical concentrations unclear
“The overall pharmacodynamic effect of the combination of OLZ, SAM, and all major metabolites at clinically relevant concentrations is unclear.”
Flexibilityopen answer page →
Flexibility accepted
OtherAccepted
No new olanzapine nonclinical studies; olanzapine pharmacology, genotoxicity, carcinogenicity and DART data taken from the approved Zyprexa label
Why: Zyprexa is the listed drug for this 505(b)(2) application · Within the guideline
“Nonclinical data describing the primary pharmacodynamics, metabolism, genotoxicity, carcinogenicity, and developmental and reproductive toxicity of OLZ will be taken from the approved label of Zyprexa, the listed drug for this 505(b)(2) NDA.”
Impurity or metaboliteAcceptedBeyond the letter
Major human metabolite RDC-1066 found late and not measured in pivotal toxicity studies; exposures estimated from later GLP PK bridging studies
Why: GLP PK bridging studies in rats, mice, dogs and rabbits provided metabolite exposure data · Pharmacology or kinetics
“Metabolite RDC-1066 was discovered in human plasma late in clinical development and was not measured in initial nonclinical toxicity studies. Therefore, a series of nonclinical GLP PK bridging studies were conducted in rats, mice, dogs, and rabbits administered oral doses of SAM for 5 to 14 consecutive days”
“The safety of the major human metabolites, RDC-9986 and RDC-1066, was adequately assessed in nonclinical species for chronic general toxicity, reproductive toxicity, and carcinogenicity.”
Safety marginVerdict not stated
Samidorphan rat NOAEL 5 mg/kg/day at 0.4 times the MRHD (AUC) in males
“The no observed adverse effect level (NOAEL) for SAM in rats is 5 mg/kg/day, which is 0.4 and 5 times the MRHD in males and females, respectively based on AUC.”
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