Nurtec ODT
rimegepant
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 cynomolgus monkey
“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Why that species
Monkey CGRP receptor affinity similar to human; rodent affinity >1,300-fold lower, so rat is insensitive
“Comparing activity across species, rimegepant exhibits similar receptor affinities at both human (Ki of 33 pM) and nonhuman primate (marmoset (92 pM) and cynomolgus monkey (60 pM)) CGRP receptors, with more than 1,300-fold less activity at dog (43 nM), rat (209 nM) and mouse (104 nM) CGRP receptors as compared to human.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Doses of 0, 5, 15, and 50 mg/kg were evaluated in the pivotal 9-month study; there were no adverse findings. The NOAEL for orally-administered rimegepant in monkey was 50 mg/kg.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Pivotal GLP studies
6-month rat and 9-month cynomolgus monkey oral studies
“Oral toxicology studies of up to 6 and 9 months’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Route in tox
Oral
“All studies used the oral application, the intended clinical route of administration of rimegepant.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and rat bone marrow micronucleus assays
“BHV-3000 was negative in Ames, chromosomal aberration, and rat bone marrow micronucleus assays.”
Carcinogenicity
26-week Tg.rasH2 mouse and 2-year rat: no drug-induced tumors
“Based on a review by the CDER Division of Biometrics, BHV-3000 did not induce tumor formation in the 26-week and 2-year carcinogenicity studies in TgRasH2 mice (0, 30, 100 300 mg/kg) and SD rats (0, 5, 15, 45 mg/kg), respectively.”
Reproductive & developmental
Rat fertility: uterine atrophy >25 mg/kg, reduced conception at 150 mg/kg; no embryofetal toxicity in rat or rabbit
“Two fertility studies in SD rat indicated uterine atrophy at doses greater than 25 mg/kg, and decreased conception and increased pre-implantation loss at 150 mg/kg. There was no embryofetal toxicity in rat or rabbit.”
Safety pharmacology
No CNS, cardiovascular or respiratory effects; hERG and sodium channel IC50 >30 µM
“There were no effects of BHV-3000 on CNS, cardiovascular, or respiratory safety pharmacology endpoints, and the IC50 for hERG or sodium ion channels was estimated to be in excess of 30 uM.”
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 Nurtec ODT 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: Rat: liver vacuolation at all doses, no NOAEL; monkey 9-month NOAEL 15 mg/kg (weight gain decreases) (FDA pharmacology/toxicology review, p. 9)
NOAEL / key findings
Rat: liver vacuolation at all doses, no NOAEL; monkey 9-month NOAEL 15 mg/kg (weight gain decreases)
“based on liver vacuolation at all doses (0, 5, 20, or 45 mg/kg) in the 6-month study, a NOAEL was not established in rats. The primary toxicity in monkeys consisted of decreases in weight gain; based on this finding, the NOAEL for daily administration of BHV-3000 for 9 months was 15 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
No effects on the immune system in pivotal studies
“Further, no hormonal perturbation, histopathological changes in endocrine or reproductive organs or effects on the immune system were observed in pivotal non-clinical studies.”
Biodistribution & persistence
Wide extravascular distribution in pigmented and albino rats; likely melanin binding
“A single-dose tissue distribution study in pigmented and albino rats demonstrated that rimegepant is widely distributed extravascularly and likely binds to melanin.”
Modality-specific risk
Intravascular hemolysis/anemia in rat and monkey
“It is difficult to dismiss this finding as not drug-related, considering evidence of intravascular hemolysis in other studies of rimegepant in monkey and rat in the absence of microscopic findings.”