activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumorgrowth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the

combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutanthuman melanoma xenografts in mice compared to either drug alone.

12.2 Pharmacodynamics

Cardiac Electrophysiology Following MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed.

12.3 Pharmacokinetics

The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. Aftertwice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the

concentration-time curve (AUC) is < 40% at steady state. The systemic exposure of binimetinib isapproximately dose proportional.

Absorption

After oral administration, at least 50% of the binimetinib dose was absorbed with a median time tomaximum concentration (Tmax) of 1.6 hours.

Effect of Food

The administration of a single dose of MEKTOVI 45 mg with a high-fat, high-calorie meal (consisting ofapproximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in

healthy subjects had no effect on binimetinib exposure.

Distribution

Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. The geometricmean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%). 

EliminationThe mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F)is 20.2 L/h (24%).

Metabolism

The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinibmetabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss

of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled

binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable tobinimetinib.

Excretion

Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged)of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the

urine.

Specific Populations

Age (20 to 94 years), sex, or body weight do not have a clinically important effect on the systemic exposureof binimetinib. The effect of race or ethnicity on the pharmacokinetics of binimetinib is unknown.

Hepatic Impairment: No clinically meaningful changes in binimetinib exposure (AUC and Cmax) wereobserved in subjects with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 × ULN and any AST or total

bilirubin ≤ ULN and AST > ULN) as compared to subjects with normal liver function (total bilirubin ≤ ULNand AST ≤ ULN). A 2-fold increase in AUC was observed in subjects with moderate (total bilirubin > 1.5