Summary of Drug Interactions for Binimetinib
1. Drugs metabolized by hepatic microsomal enzymes: CYP3A4 substrates: No pharmacokinetic interactions have been observed to date.
2. Drugs affecting uridine diphosphate glucuronosyltransferase: UGT1A1 inhibitors: No clinically important pharmacokinetic interactions are expected. UGT1A1 inducers: No clinically important pharmacokinetic interactions are expected.
3. Drugs transported by organic cation transporters: OCT1 or OCT2 substrates: No clinically important pharmacokinetic interactions are expected.
Specific Drug Interactions with Binimetinib
1. Atazanavir: Pharmacokinetic modeling suggests no significant effect on binimetinib peak concentration.
2. Smoking: No significant effect on binimetinib systemic exposure.
3. Encorafenib: No significant effect on binimetinib systemic exposure.
4. Midazolam: No significant effect on midazolam systemic exposure.
5. Rabeprazole: No significant effect on the pharmacokinetics of binimetinib and M3.
Pharmacokinetics of Binimetinib
1. Absorption
Bioavailability ≥50%.
After oral administration, peak plasma concentration is reached at approximately 1.6 hours.
After single or repeated doses of binimetinib 5–80 mg or 5–60 mg once daily, systemic exposure and peak plasma concentration are dose-proportional.
Food: A high-fat, high-calorie meal does not affect exposure.
2. Special Populations
Mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN, or total bilirubin > ULN but ≤1.5× ULN with any AST): systemic exposure similar to that in patients with normal hepatic function.
Moderate hepatic impairment (total bilirubin >1.5× ULN but ≤3× ULN with any AST): systemic exposure is 80% higher than in patients with normal hepatic function.
Severe hepatic impairment (total bilirubin >3× ULN with any AST): systemic exposure is 110% higher than in patients with normal hepatic function.
Severe renal impairment (estimated GFR ≤29 mL/min/1.73m²): systemic exposure similar to that in patients with normal renal function.
Age (20–94 years), sex, body weight, and UGT1A1 genotype have no clinically important effect on binimetinib pharmacokinetics.
3. Distribution
Extent: It is unknown whether it is secreted into human milk.
Plasma protein binding: 97%.
4. Elimination
Metabolism: Mainly metabolized by UGT1A1, and to a lesser extent by CYP1A2 and CYP2C19.
Elimination routes: Mainly eliminated via feces (62%) and urine (31%) as metabolites.
Half-life: 3.5 hours.
5. Stability
Oral tablets: Store at 20–25°C (excursions permitted between 15–30°C).
