Effect of CYP enzymes on binimetinib

In vitro, CYP1A2 and CYP2C19 catalyse the formation of the active metabolite, AR00426032 (M3) by oxidative N-desmethylation.

Effect of binimetinib on CYP substrates

Binimetinib is a weak reversible inhibitor of CYP1A2 and CYP2C9.

Effect of transporters on binimetinib

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.

Effect of binimetinib on transporters

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.

Special populations

Age, body weight

Based on a population pharmacokinetic analysis, age or body weight do not have a clinically important effect on the systemic exposure of binimetinib.

Gender

Based on a population pharmacokinetic (PK) analysis, the PK of binimetinib were similar in males as compared with females.

Race

There are insufficient data to eva luate potential differences in the exposure of binimetinib by race or ethnicity.

Hepatic impairment

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 (see section 4.2). This increase expends to three fold in both moderate and severe hepatic impairment when considering unbound binimetinib exposure (see section 4.2).

Gilbert's syndrome

Binimetinib has not been eva luated 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.

Renal impairment

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 eva luated clinically.

5.3 Preclinical safety data