Age (19 to 89 years), sex, body weight, mild hepatic impairment (Child-Pugh Class A), and mild ormoderate renal impairment (CLcr 30 to < 90 mL/min) do not have a clinically meaningful effect on the

pharmacokinetics of encorafenib. The effect of race or ethnicity, moderate or severe hepatic impairment(Child-Pugh Class B or C), and severe renal impairment (CLcr < 30 mL/min) on encorafenib

pharmacokinetics have not been studied.

Drug Interaction Studies

Clinical Studies

Effect of CYP3A4 Inhibitors on Encorafenib: Coadministration of a strong (posaconazole) or moderate(diltiazem) CYP3A4 inhibitor with BRAFTOVI increased the AUC of encorafenib by 3- and 2-fold,

respectively, and increased the Cmax by 68% and 45%, respectively, after a single BRAFTOVI dose of50 mg (0.1 times the recommended dose).

Effect of CYP3A4 Inducers on Encorafenib: The effect of coadministration of a CYP3A4 inducer onencorafenib exposure has not been studied. In clinical trials, steady-state encorafenib exposures were lower

than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.

Effect of Acid Reducing Agents on Encorafenib: Coadministration of a proton pump inhibitor, rabeprazole,had no effect on AUC and Cmax of encorafenib.

Combination Treatment: Coadministration of BRAFTOVI (UGT1A1 inhibitor) with binimetinib(UGT1A1 substrate) had no effect on binimetinib exposure.

In Vitro Studies

Effect of Encorafenib on CYP/UGT Substrates: Encorafenib is a reversible inhibitor of UGT1A1, CYP1A2,CYP2B6, CYP2C8/9, CYP2D6, and CYP3A, and a time-dependent inhibitor of CYP3A4 at clinically

relevant plasma concentrations. Encorafenib induced CYP2B6, CYP2C9, and CYP3A4 at clinically relevantplasma concentrations.

Effect of Transporters on Encorafenib: Encorafenib is a substrate of P-glycoprotein (P-gp). Encorafenib isnot a substrate of breast cancer resistance protein (BCRP), multidrug resistance-associated protein

2 (MRP2), organic anion transporting polypeptide (OATP1B1, OATP1B3) or organic cation transporter(OCT1) at clinically relevant plasma concentrations.

Effect of Encorafenib on Transporters: Encorafenib inhibited P-gp, BCRP, OCT2, organic anion transporter(OAT1, OAT3), OATP1B1, and OATP1B3, but not OCT1 or MRP2 at clinically relevant plasma

concentrations. 

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studieseva luating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in

bone marrow of rats.

No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study inrats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in

epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinicaldose based on AUC. No effects on reproductive organs were observed in either sex in any of the non-human

primate toxicity studies.

13.2 Animal Toxicology and/or Pharmacology

Adverse histopathology findings of hyperplasia and hyperkeratosis occurred in the stomach of rats atencorafenib doses of 20 mg/kg/day (approximately 14 times the human exposure at the 450 mg clinical dose