Gomekli
mirdametinib
Species
RatDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Exploratory studies were conducted in mice, rats, dogs, and monkeys, while definitive toxicity studies were conducted in rats and dogs.”
Why that species
PK and metabolism properties compared across species
“The rat and dog were selected as the general toxicology species based on mirdametinib’s PK and metabolism properties compared across species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Mirdametinib was administrated for 13 weeks at dose of 0.1, 0.3 and 1 mg/kg/day (same doses used in the 4-weeks study).”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“Pivotal studies were performed in rats and dogs up to 3 months.”
Pivotal GLP studies
Pivotal oral studies in rats and dogs up to 3 months; no chronic studies
“Pivotal studies were performed in rats and dogs up to 3 months. No chronic studies were performed.”
Route in tox
Oral (gavage)
“Studies were based on daily oral (gavage) dosing with a limited number of studies involving IV administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative Ames; not clastogenic in vitro or in rat chromosome aberration assay; positive rat micronucleus
“Mirdametinib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow chromosomal aberration assay. Mirdametinib was positive in the in vivo micronucleus assay in rats.”
Carcinogenicity
6-month rasH2 mouse: not carcinogenic up to 5 mg/kg/day
“Mirdametinib was not carcinogenic in a 6-month study in transgenic rasH2 mice that received oral doses up to 5 mg/kg/day”
Reproductive & developmental
Rat and rabbit dose-range EFD: embryofetal lethality at non-maternotoxic 0.64 and 0.3 mg/kg/day
“In the dose-range finding embryo-foetal development studies, embryofoetal lethality was observed from the non-maternotoxic dose levels of 0.64 and 0.3 mg/kg/day in rats and rabbits, respectively.”
Safety pharmacology
hERG IC50 >100 µM (39.5% inhibition at 100 µM)
“Mirdametinib at 100 µM reduced significantly the mean hERG current amplitude by 39.5% (IC50 >100 µM).”
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 Gomekli 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 NOAEL 0.1 mg/kg/day (males) and 0.3 mg/kg/day (females), at exposures below clinical exposure (EMA assessment report, p. 32)
NOAEL / key findings
Rat NOAEL 0.1 mg/kg/day (males) and 0.3 mg/kg/day (females), at exposures below clinical exposure
“The determined NOAEL was 0.1 mg/kg/day in male rats and 0.3 mg/kg/day in female rats. Exposures at these doses are below the clinical predicted exposure at the intended posology.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid hyperplasia, lymphoid depletion and increased plasma cells in lymph nodes of rats and dogs
“findings correlated with histologic signs in the lymph nodes in the 3-month studies in rats and dogs, including minimal to moderate lymphoid hyperplasia, lymphoid depletion, and increases in plasma cells, as well as hypocellularity in rats.”
Biodistribution & persistence
Rat QWBA: peak tissue levels within 4 h after oral dosing; no retention in melanin-containing tissues
“For all tissues, the highest measured concentrations were observed within 4 hours and 0.5 hours post dose for the oral and IV routes, no specific retention was observed in melanin-containing tissues.”
Modality-specific risk
Embryofetal lethality (selective developmental toxicant)
“Overall, mirdametinib is considered as a selective developmental toxicant, and the clinical relevance of drug-induced embryofoetal lethality identified in rats and rabbits cannot be excluded.”