Sunosi
solriamfetol
Species
RatMouseDog
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 (plus 3-month mouse)
“Pivotal repeat-dose toxicity studies have been performed in mice (up to 3 months), rats (up to 6 months with a 3-month recovery period) and dogs (up to 12 months with a 13 weeks recovery period).”
Why that species
Dog metabolism similar to human (limited hepatic metabolism, mostly renal excretion of parent); no unique human metabolite
“The in vivo metabolism profiles of solriamfetol are similar between dogs and humans, for which limited hepatic metabolism is observed and the majority of the drug is excreted unchanged in the urine.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Rats: In a pivotal 6-month repeat-dose toxicity study with a 3-month recovery period, daily oral doses of 29, 253 and 505 (reduced to 379 at study day 93 because of overt toxicity) mg/kg solriamfetol produced”
Species: general tox
Rat (6-month) and dog (12-month); mouse up to 3 months
“Pivotal repeat-dose toxicity studies have been performed in mice (up to 3 months), rats (up to 6 months with a 3-month recovery period) and dogs (up to 12 months with a 13 weeks recovery period).”
Species: DART
Rat and/or rabbit (complete DART battery)
“a complete battery of reproductive and developmental toxicology studies in the rat and/or rabbit”
Species: carcinogenicity
Rat and mouse (2-year)
“Two-year carcinogenicity studies were conducted in rats and mice.”
Surrogate used in
No surrogate used; solriamfetol tested directly
“Rats: In a pivotal 6-month repeat-dose toxicity study with a 3-month recovery period, daily oral doses of 29, 253 and 505 (reduced to 379 at study day 93 because of overt toxicity) mg/kg solriamfetol produced”
Study lengthopen answer page →
Longest pivotal study
52 (12-month dog)
“Pivotal repeat-dose toxicity studies have been performed in mice (up to 3 months), rats (up to 6 months with a 3-month recovery period) and dogs (up to 12 months with a 13 weeks recovery period).”
Pivotal GLP studies
6-month rat and 12-month dog oral studies, plus 3-month mouse
“Pivotal repeat-dose toxicity studies have been performed in mice (up to 3 months), rats (up to 6 months with a 3-month recovery period) and dogs (up to 12 months with a 13 weeks recovery period).”
Route in tox
Oral
“Rats: In a pivotal 6-month repeat-dose toxicity study with a 3-month recovery period, daily oral doses of 29, 253 and 505 (reduced to 379 at study day 93 because of overt toxicity) mg/kg solriamfetol produced”
Skipped studiesopen answer page →
Genotoxicity
Negative in an adequate battery of genotoxicity assays
“Solriamfetol was non-genotoxic in an adequate battery of genotoxicity assays.”
Carcinogenicity
Rat and mouse oral studies: no tumors at up to ~3.5x (rat) and 9x (mouse) the MRHD by AUC
“Solriamfetol was not carcinogenic and did not induce tumors in rats or mice when administered orally at doses up to approximately 3.5- and 9- times the MRHD of 300 mg/day to rats and mice, respectively, based on AUC.”
Reproductive & developmental
Rat and rabbit EFD: maternal and fetal toxicity; teratogenic in rats at 9.5x and rabbits at >=2.5x MRHD
“In embryo-fetal developmental studies, oral administration of solriamfetol during organogenesis caused maternal and fetal toxicities in rats and rabbits at doses ≥ 2- and 2.5- times- and was teratogenic at doses 9.5- and ≥ 2.5- times, respectively, the MRHD”
Safety pharmacology
Cardiovascular, respiratory and CNS studies: no severe adverse effects at clinically relevant doses
“The safety pharmacology of solriamfetol was evaluated in the cardiovascular, respiratory, and CNS systems. No severe adverse effects were identified at the clinically relevant doses.”
Genotox: Ames
Negative
“Solriamfetol plate was not mutagenic in any of the tester strains in the presence or absence of metabolic activation.”
Genotox: in vitro mammalian
Chromosomal aberration in human lymphocytes: negative
“Solriamfetol was not clastogenic in a valid in vitro mammalian cell chromosome aberration assay.”
Genotox: in vivo
Oral mouse micronucleus (up to 250 mg/kg): negative
“Solriamfetol, when orally administered at doses up to 250 mg/kg, was negative in a valid in vivo mouse micronucleus study.”
Carcinogenicity model
Oral mouse (up to 104 weeks) and rat (up to 101 weeks)
“Long-term oral carcinogenicity studies have been performed in mice, treated with daily solriamfetol doses of 20, 65 and 200 mg/kg for up to 104 weeks, and in rats, treated with daily solriamfetol doses of 35, 80 and 200 mg/kg for up to 101 weeks.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies completed before approval; ECAC judged them adequate
“The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”
hERG / QT
No significant hERG inhibition: 5%, 13% and 19% at 0.1, 1 and 10 µM
“Solriamfetol at concentrations of 0.1, 1, and 10 µM only induced 5%, 13%, and 19% inhibition of the hERG current, whereas the positive control astemizole induced 93% inhibition of hERG current at 10 nM.”
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 Sunosi 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: Lung target organ in rats and dogs: alveolar macrophages and phospholipidosis-like inclusions without functional adversity (FDA pharmacology/toxicology review, p. 11)
NOAEL / key findings
Lung target organ in rats and dogs: alveolar macrophages and phospholipidosis-like inclusions without functional adversity
“In both rats and dogs, the target organ of the drug is the lung with elevated macrophages and phospholipidosis-like inclusion bodies (without functional adversity in the lung).”
Risksopen answer page →
Immune & cytokine safety
Dose-dependent changes in immune cell counts and immune organ weight/morphology, most prominent in rats
“Concerning the immune system, dose-dependent effects of solriamfetol on numbers of immune cells and morphology/weight of immune-system related organs (most prominent in rat studies) were observed.”
Biodistribution & persistence
Extensive distribution into pigmented and non-pigmented tissues, including brain
“After oral administration, solriamfetol was extensively distributed into pigmented and non-pigmented tissues, including the brain.”
Modality-specific risk
Stimulant-like CNS toxicity, the most prominent effect across species
“In nonclinical toxicology studies in the mouse, rat, dog, and rabbit, the most prominent drug-related effects of solriamfetol are observed in the CNS, most likely due to its stimulant-like pharmacology.”
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
- Blood Pressure and Heart Rate Increases
- Psychiatric Symptoms
CardiovascularPsychiatric
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 Sunosi 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: Lung target organ in rats and dogs: alveolar macrophages and phospholipidosis-like inclusions without functional adversity (FDA pharmacology/toxicology review, p. 11)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
12-month dog (oral) with 13-week recovery
“Dogs: In a pivotal 12-month repeat-dose toxicity study with a 13-week recovery period, solriamfetol given in two divided daily oral doses of (total) 8, 21, or 42 mg/kg caused hyperactivity/agitation and transient weight loss at all dose levels”
Pivotal GLP studies
6-month rat and 12-month dog oral studies, plus 3-month mouse
“Pivotal repeat-dose toxicity studies have been performed in mice (up to 3 months), rats (up to 6 months with a 3-month recovery period) and dogs (up to 12 months with a 13 weeks recovery period).”
DART package
Species: DART
Rat and/or rabbit (complete DART battery)
“a complete battery of reproductive and developmental toxicology studies in the rat and/or rabbit”
Reproductive & developmental
Rat and rabbit EFD: maternal and fetal toxicity; teratogenic in rats at 9.5x and rabbits at >=2.5x MRHD
“In embryo-fetal developmental studies, oral administration of solriamfetol during organogenesis caused maternal and fetal toxicities in rats and rabbits at doses ≥ 2- and 2.5- times- and was teratogenic at doses 9.5- and ≥ 2.5- times, respectively, the MRHD”
PPND / ePPND: when
PPND in rat completed and reviewed in the NDA
“In the pre- and post-natal developmental toxicity study in the rat, at 3.5- and 11- times the MRHD based on mg/m2 body surface area, solriamfetol caused maternal toxicities of decreased body weight gain, food consumption, and hyperpnea.”
Carcinogenicity
Species: carcinogenicity
Rat and mouse (2-year)
“Two-year carcinogenicity studies were conducted in rats and mice.”
Carcinogenicity model
Oral mouse (up to 104 weeks) and rat (up to 101 weeks)
“Long-term oral carcinogenicity studies have been performed in mice, treated with daily solriamfetol doses of 20, 65 and 200 mg/kg for up to 104 weeks, and in rats, treated with daily solriamfetol doses of 35, 80 and 200 mg/kg for up to 101 weeks.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies completed before approval; ECAC judged them adequate
“The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL margins ~1x MRHD in dog and <1x in mouse and rat (AUC)
“The safety margins relative to the MRHD of 300 mg at the no observed adverse effect levels (NOAELs) in the pivotal general toxicology studies were approximately 1 in the dog and < 1 in the mouse and rat, based on AUC.”
NOAEL / key findings
Lung target organ in rats and dogs: alveolar macrophages and phospholipidosis-like inclusions without functional adversity
“In both rats and dogs, the target organ of the drug is the lung with elevated macrophages and phospholipidosis-like inclusion bodies (without functional adversity in the lung).”
Efficacy evidenceopen answer page →
Efficacy evidence
Hypocretin/ataxin-3 transgenic narcolepsy mice: continuous wakefulness induced
“In a proof of concept study in hypocretin/ataxin-3 transgenic mice (mouse model of narcolepsy), solriamfetol dose-dependently induced continuous wakefulness during the resting (light) and active (dark) phase.”
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
EMA: narcolepsy mouse results confirm potential effectiveness in treating EDS
“These results confirm a potential effectiveness in treating EDS in narcolepsy.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin at general toxicology NOAELs: about 1 in dog and below 1 in mouse and rat (AUC)
“The safety margins relative to the MRHD of 300 mg at the no observed adverse effect levels (NOAELs) in the pivotal general toxicology studies were approximately 1 in the dog and < 1 in the mouse and rat, based on AUC.”
GLPAcceptedBeyond the letter
In vitro hERG and isolated cardiac tissue studies not GLP-compliant and not repeated under GLP
Why: QTc-prolonging potential already characterised qualitatively and quantitatively · Weight of evidence
“Since the QTc-prolonging potential of solriamfetol has been qualitatively and quantitatively characterized on basis of the aforementioned studies, the position of the Applicant not to repeat in vitro hERG and isolated cardiac tissue studies under formally GLP-compliant conditions appears acceptable.”
DARTAcceptedBeyond the letter
Rabbit embryo-fetal development study without toxicokinetics
Why: Drug-related clinical signs and body weight changes qualitatively confirm exposure · Other reason
“Although TK is not performed, drug-related clinical signs and changes in body weight gain and food consumption were observed and were consistent with previous repeat dose studies in the rabbits, therefore qualitatively confirming drug exposure.”
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