Enasidenib

Enasidenib is a small molecule inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme. Enasidenib targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme by enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, enasidenib decreased 2-HG levels, reduced blast counts and increased percentages of mature myeloid cells.

Cardiac Electrophysiology

The potential for QTc prolongation with enasidenib was evaluated in an open-label study in patients with advanced hematologic malignancies with an IDH2 mutation. Based on the QTc data for a single dose of 30 mg to 650 mg and multiple doses of 100 mg daily in the fasted state, no large mean changes in the QTc interval (>20 ms) were observed following treatment with enasidenib.

The peak plasma concentration (C_max) is 1.4 mcg/mL [% coefficient of variation (CV%) 50.2] after a single dose of 100 mg, and 13.1 mcg/mL (CV% 44.8) at steady state for 100 mg daily. The area under concentration time curve (AUC) of enasidenib increases in an approximately dose proportional manner from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended dosage) daily dose. Steady-state plasma levels are reached within 29 days of once-daily dosing. Accumulation is approximately 10-fold when administered once daily.

Absorption

The absolute bioavailability after 100 mg oral dose of enasidenib is approximately 57%. After a single oral dose, the median time to C_max (T_max) is 4 hours.

Distribution

The mean volume of distribution (Vd) of enasidenib is 55.8 L (CV% 29). Human plasma protein binding of enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro.

Enasidenib is not a substrate for P-glycoprotein or BCRP, while AGI-16903 is a substrate of both P-glycoprotein and BCRP. Enasidenib and AGI-16903 are not substrates of MRP2, OAT1, OAT3, OATP1B1, OATP1B3, and OCT2.

Elimination

Enasidenib has a terminal half-life of 7.9 days and a mean total body clearance (CL/F) of 0.70 L/hour (CV% 62.5).

Metabolism

Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated metabolite, represented 10% of the circulating radioactivity.

In vitro studies suggest that metabolism of enasidenib is mediated by multiple CYP enzymes (e.g., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UGTs (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). Further metabolism of the metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9).

Excretion

Eighty-nine percent (89%) of enasidenib is eliminated in feces and 11% in the urine. Excretion of unchanged enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine.

Specific Populations

No clinically meaningful effect on the pharmacokinetics of enasidenib was observed for the following covariates: age (19 years to 100 years), race (White, Black, or Asian), mild hepatic impairment [defined as total bilirubin ≤ upper limit of normal (ULN) and aspartate transaminase (AST) >ULN or total bilirubin 1 to 1.5 times ULN and any AST], renal impairment (defined as creatinine clearance ≥30 mL/min by Cockcroft-Gault formula), sex, body weight (39 kg to 136 kg), and body surface area.

Drug Interaction Studies

In vitro studies suggest that enasidenib inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and UGT1A1. Enasidenib inhibits P-gp, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2, but not MRP2 or OAT3. Enasidenib induces CYP2B6 and CYP3A4.

In vitro studies suggest that the metabolite AGI-16903 inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2, but not P-gp, MRP2, or OATP1B3.

Coadministration of enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time.