Dayvigo
lemborexant
Species
MonkeyRat
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 monkey
“The general toxicity of orally administered lemborexant at doses up to 1000 mg/kg/day was evaluated in rats and monkeys up to 6 months and 9 months in duration, respectively.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Study title/ study number: E2006: A 39-Week Oral Toxicity Study in Monkeys/ 6700074”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“The general toxicity of orally administered lemborexant at doses up to 1000 mg/kg/day was evaluated in rats and monkeys up to 6 months and 9 months in duration, respectively.”
Pivotal GLP studies
13/26-week rat and 39-week monkey studies
“The conducting laboratories were different for the 13/26- week rat study and 39-week monkey study.”
Route in tox
Oral
“The general toxicity of orally administered lemborexant at doses up to 1000 mg/kg/day was evaluated in rats and monkeys up to 6 months and 9 months in duration, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma TK and in vivo rat micronucleus assays
“Lemborexant was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or in the in vitro mouse lymphoma thymidine kinase assay, and was not clastogenic in the in vivo rat micronucleus assay.”
Carcinogenicity
2-year rat and 6-month Tg rasH2 mouse: no drug-related tumors
“Lemborexant did not increase the incidence of tumors in a 6-month carcinogenicity study in Tg ras H2 transgenic mice or in a 2-year study in rats and therefore is considered non-carcinogenic.”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND; irregular estrous cycles and lower pregnancy rate at >=100 mg/kg/day
“Reproductive and developmental toxicity was assessed in fertility studies in male and female rats, embryo-fetal development studies in pregnant rats and rabbits, and a pre- and post-natal development study in rats. Irregular estrous cycles and decreased pregnancy rates were observed in female rats at doses ≥100 mg/kg/day.”
Safety pharmacology
QTc prolongation in telemetered monkeys at >=30 mg/kg (~22x human Cmax at MRHD)
“Lemborexant prolonged the QTc interval in conscious telemetered monkeys after single doses ≥30 mg/kg, which produces exposures approximately 22-fold the steady state Cmax value in humans at the maximum recommended human dose (MRHD).”
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 Dayvigo 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: NOAEL rat 100 (male) and 30 (female) mg/kg/day, 41x and 12x MRHD AUC (FDA multi-discipline review, p. 48)
NOAEL / key findings
NOAEL rat 100 (male) and 30 (female) mg/kg/day, 41x and 12x MRHD AUC
“The NOAEL in male and female rats is 100 and 30 mg/kg/day which are 41 times and 12 times the MRHD based on AUC, respectively.”
Risksopen answer page →
Immune & cytokine safety
No drug-related findings in immune function assessments (immunophenotyping, NK activity, granulocyte function, cytokine release)
“There were no significant drug-related findings in any immune function assessments: Immunophenotyping, natural killer cell activity, peripheral blood granulocytes functions, cytokine release.”
Biodistribution & persistence
Rapid wide distribution, highest in liver; no melanin accumulation; crosses BBB with CSF above plasma
“Lemborexant is rapidly and extensively distributed to tissues in rats and monkeys with the highest levels found in liver and no accumulation in melanin-containing tissues in rats. Lemborexant and its metabolites readily cross the blood brain barrier and drug concentrations in cerebral spinal fluid are higher than that of plasma.”
Modality-specific risk
Bone and teeth toxicity in rats from fluoride released by metabolism (fluorosis); low human relevance
“The observed bone and teeth toxicity in rats may be the result of fluorosis caused by the release of fluoride during the metabolism of lemborexant; an increase in fluoride levels was observed in bones of rats following daily administration of lemborexant.”