Reyvow
lasmiditan
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
“General Toxicology: the oral toxicity of lasmiditan was tested in Sprague-Dawley rat (4-week + 2-week recovery, 13-week + 4-week recovery, and 26-week + 8-week recovery) and Beagle dog (2-week, 4-week + 2-week recovery, 13-week + 4-week recovery, and 39-week + 8-week recovery).”
Why that species
Major human metabolites M8 and M18 are produced in mouse, rat, rabbit and dog
“In humans, the major circulating metabolites are M8 and[S,R]-M18, which account for 47.5 and 10.5% of drug-related material in circulation. Both metabolites were produced in mouse, rat, rabbit, and dog.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In rat, lasmiditan was administered at doses up to 100 (4-week study) or 200 (13- and 26-week studies) mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“In the 39-week study, the high dose was reduced to 40 mg/kg/day because of intolerability.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“General Toxicology: the oral toxicity of lasmiditan was tested in Sprague-Dawley rat (4-week + 2-week recovery, 13-week + 4-week recovery, and 26-week + 8-week recovery) and Beagle dog (2-week, 4-week + 2-week recovery, 13-week + 4-week recovery, and 39-week + 8-week recovery).”
Route in tox
Oral
“All pivotal in vivo nonclinical studies were conducted using oral administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and mouse bone marrow micronucleus assays
“Lasmiditan was negative in adequately designed and conducted in vitro (bacterial reverse mutation, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity
2-year rat and 6-month Tg rasH2 mouse: not carcinogenic
“Lasmiditan was not carcinogenic in 2-year rat or 6-month Tg rasH2 mouse studies.”
Reproductive & developmental
Rabbit EFD: malformations, embryofetal mortality and reduced fetal weight at a maternally toxic dose
“Oral administration of lasmiditan (0, 50, 75, or 115 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in malformations (skeletal and visceral), increases in skeletal variations and embryofetal mortality, and decreased fetal body weight were observed at the highest dose tested, which was associated with maternal toxicity.”
Safety pharmacology
hERG IC50 ~3.0 µM (>4-fold human Cmax); ECG, respiratory and vasoactivity assessments negative
“In hERG assays, IC50s for lasmiditan (~3.0 µM) and metabolites M8 and M18 (>30 µM) exceeded 4-fold the plasma Cmax in humans following oral administration of 200 mg. ECG, respiratory, and vasoactivity assessments were negative.”
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 Reyvow 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: 39-week dog: tremors and hypoactivity; NOAEL 30 mg/kg (8-fold AUC margin) (FDA pharmacology/toxicology review, p. 11)
NOAEL / key findings
39-week dog: tremors and hypoactivity; NOAEL 30 mg/kg (8-fold AUC margin)
“In the 39-week toxicology study in dog, there were lasmiditan-related tremors and hypoactivity. The safety margin was 8-fold compared to the maximum human dose based on AUC at the NOAEL of 30 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
Splenic marginal-zone lymphoid depletion and thymic involution at high dose in rats
“In all HD animals, hepatocellular hypertrophy, foamy alveolar macrophages, epithelial vacuolation in the seminal vesicle, vacuolation and lymphoid depletion of the marginal zone in the spleen, cortical hypertrophy of the adrenals, decreased hematopoietic tissue in the bone marrow, and thymic involution were also observed”
Biodistribution & persistence
Crosses blood-brain barrier (brain:plasma ~3); highest concentrations in urinary bladder and uveal tract
“Distribution studies (with [14C]lasmiditan) in rat show that lasmiditan crosses the blood brain barrier, with brain to plasma ratios of approximately 3 over a 24-hour period after IV dosing. The highest concentrations of [14C]lasmiditan were found in the urinary bladder and uveal tract of the eye.”
Modality-specific risk
Potential for coronary artery vasoconstriction
“In addition, the sponsor conducted nonclinical studies to address concerns regarding the potential for lasmiditan to cause coronary artery vasoconstriction.”