PubChem compound: 9826528
Mirdametinib is a selective, non‑competitive inhibitor of mitogen‑activated protein kinase kinases 1 and 2 (MEK1/2). Mirdametinib blocks MEK activity and the rat sarcoma (RAS)‑rapidly accelerated fibrosarcoma (RAF)‑MEK pathway. Therefore, MEK inhibition blocks proliferation and survival of tumour cells in which the RAF‑MEK‑extracellular related kinase (ERK) pathway is activated.
The pharmacokinetics of mirdametinib was studied in healthy subjects, NF1‑PN patients and advanced cancer patients.
Following multiple oral doses at 2 mg/m² twice daily, the geomean [geometric % coefficient of variation (CV)] Cmax and AUClast in adult participants with NF1‑PN were 188 (52%) ng/mL and 431 (43%) ng × h/mL, respectively. Following oral dosing, mirdametinib produced peak steady state plasma concentrations (Tmax) approximately one hour post‑dose.
In healthy adult subjects at a single dose of 20 mg, co‑administration of mirdametinib with a high‑fat, high‑calorie meal resulted in 43% lower Cmax, while the area under the concentration‑time curve (AUC) was not significantly changed (AUCinf decreased by 7%). The time to reach maximum concentration (Tmax) was delayed by approximately 3 hours. The effect on Cmax is not considered clinically relevant due to the absence of effect on overall exposure.
Following a single oral dose of 4 mg [14C]mirdametinib in healthy subjects, the mean apparent volume of distribution of mirdametinib was 255 L. Human plasma protein binding is >99%. Mirdametinib is mainly bound to human serum albumin (>99%). Binding to α1‑acid glycoprotein (AAG) ranged from 17.2% to 54.3%. The blood/plasma ratio for mirdametinib is 0.61.
Mirdametinib is highly metabolised via glucuronidation and oxidation via uridine diphosphate glucuronosyltransferase (UGT) and carboxyl esterase (CES) enzymes, resulting in M22 (a secondary O‑glucuronide metabolite) and M15 (a carboxylic acid metabolite), respectively. Less than 10% is excreted unchanged.
In vitro, mirdametinib is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Mirdametinib is an inducer of CYP3A4 in vitro, however there is a low potential for CYP3A4 induction at clinically relevant concentrations.
In vitro, mirdametinib is not an inhibitor of the isoforms UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 at clinically relevant concentrations.
In vitro studies suggest that mirdametinib and its major metabolite do not inhibit the breast cancer resistance protein (BCRP), P‑glycoprotein (P‑gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1 or MATE2K transporters.
Based on in vitro studies, mirdametinib is a substrate for BCRP and P‑gp transporters and its major metabolite is a substrate for BCRP, but they are unlikely to be clinically relevant.
In healthy adult subjects, following a single dose of 4 mg of radiolabelled mirdametinib, 68% of the dose was recovered in urine (0.7% unchanged) while 27% was recovered in faeces (8.7% unchanged in urine and faeces). The mean terminal half life is 28 hours. The apparent systemic clearance (CL/F) is 6.34 L/h.
Mirdametinib exposures, as measured by Cmax and AUCtau, generally increased dose proportionally from 1 mg QD/BID to 30 mg BID. A linear relationship between dose and exposure was verified by population pharmacokinetic analyses over the dose range of 1 mg to 20 mg mirdametinib BID. The mean accumulation ratio ranged from 1.1 to 1.9 across dose levels from 1 to 30 mg.
Steady‑state concentrations in patients with NF1‑PN are achieved on average approximately 6 days following repeat administration.
Based on population pharmacokinetic analysis, age (2 to 86 years), sex and race (72% white, 11% black or African American, and 12% Asian) do not significantly influence the pharmacokinetics of mirdametinib.
No formal pharmacokinetic studies have been conducted in patients with renal impairment. No data are available in patients with severe renal impairment or end stage renal disease (ESRD).
Patients with creatinine clearance indicative of mild or moderate renal impairment participated in mirdametinib clinical studies. Population pharmacokinetic analysis suggest that mild or moderate renal impairment (as estimated by creatinine clearance) do not impact mirdametinib exposure.
No formal pharmacokinetic studies have been conducted in patients with hepatic impairment. Population pharmacokinetic analyses in patients with mild hepatic impairment indicate no meaningful effects on exposure.
The pharmacokinetic profile in children is similar to that of adults.
Non‑clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology.
Mirdametinib was not genotoxic in a bacterial reverse mutation (Ames) assay or in an in vitro human lymphocyte chromosomal aberration assay but was equivocal in the in vivo micronucleus study and in vivo chromosomal aberrations study in rats. A genotoxicity risk in human could not be excluded at the clinical exposure range.
Mirdametinib was not carcinogenic in transgenic mice at a dose of 5 mg/kg/day (3 times the human exposure). Since a genotoxicity risk in humans could not be excluded at clinical exposure and the 2‑year rat carcinogenicity study is performed at exposures below the clinical exposure, a carcinogenicity risk could not be excluded.
In oral, repeat dose toxicity studies conducted for up to 3 months in rats and dogs, the primary toxicities due to MEK inhibition were in the skin and GI tract at doses below human exposure. In the 3‑month rat study with mirdametinib, at doses approximately equivalent to the human exposure, rats showed dysplasia in femoral epiphyseal growth plate, metaphyseal hypocellularity of the bone marrow of long bones, and metaphyseal thickening of bone trabeculae of long bones. Male rats were more sensitive to these effects. These bone effects were not seen in other species (dogs, monkeys or mice).
Reversibility of dysplasia in epiphyseal growth plate was not evaluated. In rats, systemic mineralization and ocular findings (corneal opacities and atrophy or thinning of the corneal epithelium) were observed in repeat dose toxicity studies at doses below human exposure. Increases in liver enzymes (rats) and hepatocellular necrosis (rats, mice, and dogs) were observed at exposures similar to clinical exposure. In a 2‑week study in cynomolgus monkeys, gallbladder toxicity was observed at exposures >2.5‑fold the human exposure.
CNS effects were observed in dogs in the 3‑month study at exposures approximately 1.5 times the human exposure; these effects in dogs, including impaired balance and tremors, were reversible and there was no microscopic correlate.
In a male and female rat fertility study, mirdametinib at a dose up to 1.0 mg/kg/day (approximately equivalent to the human exposure at the recommended dose based on AUC) did not affect mating performance or fertility in both sexes. In a 3‑month repeat‑dose toxicology study in rats, mirdametinib caused decreased ovarian organ weight and increased follicular cysts associated with decreases in the number of corpora lutea at doses ≥0.3 mg/kg/day (0.5 times the human exposure), as well as testicular hypocellularity and decreased weight of epididymides at 1 mg/kg/day (2.1 times the human exposure).
In preliminary embryo‑foetal developmental toxicity studies in pregnant rats and rabbits, oral dosing of mirdametinib induced postimplantation loss (early and late resorptions) and decreased foetal body weights at exposures below the human exposures at the recommended dose. In the preliminary rat study, a single foetus had extremity malformations at doses 3.6‑fold higher than the recommended human dose. Definitive embryo‑foetal development and pre‑ and post‑natal development studies were not conducted with mirdametinib.
Mirdametinib was equivocal in an in vitro mouse fibroblast phototoxicity assay at significantly higher concentrations than clinical exposures and was not retained in the skin or eyes of rats, indicating that there is low risk for phototoxicity in patients taking mirdametinib.
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