Chemical formula: C₁₇H₁₅BrF₂N₄O₃ Molecular mass: 441.233 g/mol PubChem compound: 10288191
Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. In cell free system, binimetinib inhibits MEK1 and MEK2 with the half maximal inhibitory concentration (IC50)'s in the 12-46 nM. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. In melanoma and other cancers, this pathway is often activated by mutated forms of BRAF which activates MEK. Binimetinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity. Binimetinib inhibits growth of BRAF V600 mutant melanoma cell lines and demonstrates anti-tumour effects in BRAF V600 mutant melanoma animal models.
Binimetinib and encorafenib (a BRAF inhibitor) both inhibit the MAPK pathway resulting in higher anti-tumour activity, compared to treatment with either drug alone.
The pharmacokinetics of binimetinib were studied in healthy subjects and patients with solid tumours. After repeat twice-daily dosing concomitantly with encorafenib, steady-state conditions for binimetinib were reached within 15 days with no major accumulation. The mean (CV ) Cmax,ss was 654 ng/mL (34.7) and mean AUCss was 2.35 ug.h/mL (28.0%) in combination with encorafenib as estimated by population PK modelling in patients with unresectable or metastatic BRAF V600 mutant melanoma. Binimetinib pharmacokinetics have been shown to be approximately dose-linear.
After oral administration, binimetinib is rapidly absorbed with a median Tmax of 1.5 hours. Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, at least 50% of the binimetinib dose was absorbed. Administration of a single 45 mg dose of binimetinib with a high-fat, high-calorie meal decreased the maximum binimetinib concentration (Cmax) by 17%, while the area under the concentration-time curve (AUC) was unchanged. A drug interaction study in healthy subjects indicated that the extent of binimetinib exposure is not altered in the presence of a gastric pH-altering agent (rabeprazole).
Binimetinib is 97.2% bound to human plasma proteins in vitro. Binimetinib is more distributed in plasma than blood. In humans, the blood-to-plasma ratio is 0.718. Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, the apparent volume of distribution (Vz/F) of binimetinib is 374 L.
Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, the primary biotransformation pathways of binimetinib observed in humans include glucuronidation, N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The maximum contribution of direct glucuronidation to the clearance of binimetinib was estimated to have been 61.2%. Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib. In vitro, CYP1A2 and CYP2C19 catalyse the formation of the active metabolite, which represents less than 20% of the binimetinib exposure clinically.
Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, a mean of 62.3% of the radioactivity was eliminated in the feces while 31.4% was eliminated in the urine. In urine, 6.5% of the radioactivity was excreted as binimetinib. The mean (CV ) apparent clearance (CL/F) of binimetinib was 28.2 L/h (17.5). The median (range) binimetinib terminal half-life (T1/2) was 8.66 h (8.10 to 13.6 h).
Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. In clinical study sub-analysis, however, there was no apparent relationship observed between binimetinib exposure and UGT1A1 mutation status. In addition, simulations to investigate the effect of 400 mg atazanavir (UGT1A1 inhibitor) on the exposure of 45 mg binimetinib predicted similar binimetinib Cmax in the presence or absence of atazanavir. Therefore, the extent of drug interactions mediated by UGT1A1 is minimal, and unlikely clinically relevant; however, as this has not been evaluated in a formal clinical study, UGT1A1 inducers or inhibitors should be administered with caution.
In vitro, CYP1A2 and CYP2C19 catalyse the formation of the active metabolite, AR00426032 (M3) by oxidative N-desmethylation.
Binimetinib is a weak reversible inhibitor of CYP1A2 and CYP2C9.
In vitro experiments indicate that binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Inhibition of P-gp or BCRP is unlikely to result in a clinically important increase in binimetinib concentrations as binimetinib exhibits moderate to high passive permeability.
Binimetinib is a weak inhibitor of OAT3. No clinicallly significant drug-drug interactions caused by binimetinib on other transporters is expected.
Binimetinib is metabolised by UGTs and CYP1A2 and is a substrate for Pgp. Specific inducers of these enzymes have not been studied and may result in a loss of efficacy.
Based on a population pharmacokinetic analysis, age or body weight do not have a clinically important effect on the systemic exposure of binimetinib.
Based on a population pharmacokinetic (PK) analysis, the PK of binimetinib were similar in males as compared with females.
There are insufficient data to evaluate potential differences in the exposure of binimetinib by race or ethnicity.
As binimetinib is primarily metabolised and eliminated via the liver, patients with moderate to severe hepatic impairment may have increased exposure. Results from a dedicated clinical study with binimetinib only indicate similar exposures in patients with mild impairment (Child-Pugh Class A) and subjects with normal liver function. A two-fold increase in total binimetinib exposure (AUC) was observed in patients with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment. This increase expends to three fold in both moderate and severe hepatic impairment when considering unbound binimetinib exposure.
Binimetinib has not been evaluated in patients with Gilbert’s disease. The main route of hepatic transformation of binimetinib being glucoronidation, the decision for treatement should be made by the treating physician taking into account the individual benefit-risk.
Binimetinib undergoes minimal renal elimination. Results from a dedicated clinical study showed that patients with severe renal impairment (eGFR ≤29 mL/min/1.73 m²), had a 29% increase in exposure (AUCinf), a 21% increase in Cmax, and a 22% decrease in CL/F compared to matching healthy subjects. These differences were within the variability observed for these parameters in both cohorts of this study (25% - 49%) and the variability previously observed in patient clinical studies, hence these differences are unlikely to be clinically relevant.
The effects of renal impairment on the pharmacokinetics of binimetinib in combination with encorafenib have not been evaluated clinically.
Repeated oral administration of binimetinib in rats for up to 6 months was associated with soft tissue mineralisation, gastric mucosal lesions and reversible minimal to mild clinical pathology changes at 7 to 12.5 times human therapeutic exposures. In a gastric irritation study in rats, an increased incidence of superficial mucosal lesions and of hemorrhagic ulcers were observed. In cynomolgus monkeys, oral administration of binimetinib was associated with gastro-intestinal intolerance, moderate clinical pathology changes, bone marrow hypercellularity and microscopic findings of gastrointestinal inflammation, reversible at the lowest doses which were below human therapeutic exposures.
Carcinogenic potential of binimetinib was not evaluated. Standard genotixicity studies with binimetinib were negative.
The potential embryo-foetal effects of binimetinib were evaluated in rats and rabbits. In rats, lower gestational body weight gain and fetal body weights and a decreased number of ossified fetal sternebrae were noted. No effects were noted at 14-times the human therapeutic exposure. In rabbits, mortality, maternal physical signs of toxicity, lower gestational body weight and abortion were noted. The number of viable foetuses and foetal body weights were reduced and post-implantation loss and resorptions were increased. An increased litter incidence of foetal ventricular septal defects and pulmonary trunk alterations was noted at the highest doses. No effects were observed at 3times the human therapeutic exposure.
Fertility studies were not conducted with binimetinib. In repeat-dose toxicity studies, no concern in terms of fertility was raised from pathological examination of reproductive organs in rats and monkeys.
Binimetinib has phototoxic potential in vitro.
A minimal risk for photosensitisation was shown in vivo at an oral dose providing 3.8-fold higher exposure than that achieved with the recommended dose in humans. These data indicate that there is minimal risk for phototoxicity with binimetinib at therapeutic doses in patients.
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