Idhifa (enasidenib mesylate)

Enasidenib, a potent and selective inhibitor of isocitrate dehydrogenase-2 (IDH2), is an antineoplastic agent.

Enasidenib, a potent and selective inhibitor of isocitrate dehydrogenase-2 (IDH2), is an antineoplastic agent. Isocitrate dehydrogenases (IDH) are metabolic enzymes in the citric acid cycle responsible for the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, which is essential for normal cellular processes. Approximately 15-20% of acute myeloid leukemia (AML) cases carry IDH2 mutations.

The most common IDH2 mutation is a point mutation at codon R140Q; a less frequently occurring IDH2 mutation is a point mutation at codon R172K. IDH2 mutations cause a reduction of alpha-ketoglutarate to the oncometabolite 2-hydroxyglutarate, which competitively inhibits alpha-ketoglutarate-dependent dioxygenases resulting in epigenetic dysregulation and subsequent histone and DNA hypermethylation and differentiation arrest of hematopoietic stem cells. In vitro studies indicate that enasidenib inhibits IDH2 with R140Q, R172S, or R172K mutation at approximately 40-fold lower concentrations than IDH2 wild-type enzymes.

Enasidenib has demonstrated decreased 2-hydroxyglutarate levels and induction of myeloid cell differentiation in vitro and in mice bearing tumor xenografts that expressed IDH2 mutation. Enasidenib also has demonstrated decreased 2-hydroxyglutarate levels, reduced blast cell counts, and increased percentages of mature myeloid cells in patients with AML that expressed IDH2 mutation. In the phase 1/2 study evaluating enasidenib in patients with relapsed or refractory AML, mature granulocytes retained baseline IDH2 mutations and cytogenetic abnormalities in patients who achieved remission, indicating continued differentiation of abnormal myeloblast cells into mature granulocytes.

Following oral administration of enasidenib, the absolute bioavailability of the drug is 57%. Area under the serum concentration-time curve (AUC) of enasidenib is dose proportional over the enasidenib dosage range of 50-450 mg daily. Following oral administration of a single dose, median time to peak plasma concentrations of enasidenib is 4 hours.

Repeated administration of enasidenib resulted in an approximately tenfold mean enasidenib accumulation ratio. Steady-state concentrations are reached within 29 days. Systemic exposure of enasidenib was increased by 50% when enasidenib was administered with a high-fat meal; however, this effect is not considered clinically important.

Enasidenib is metabolized to the active AGI-16903 metabolite by cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 and by uridine diphosphate-glucuronosyl transferases (UGT) 1A1, 1A3, 1A4, 1A9, 2B7, and 2B15. AGI-16903 is subsequently metabolized by CYP isoenzymes 1A2, 2C19, and 3A4 and by UGT1A1, 1A3, and 1A9. Enasidenib and AGI-16903 are highly bound (98.5 and 96.6%, respectively) to plasma proteins.

The terminal half-life of enasidenib is 7.9 days. Following administration of a radiolabeled dose of enasidenib, 89% of the radioactivity was recovered in feces (34% of the dose as unchanged drug) and 11% was recovered in urine (0.4% of the dose as unchanged drug).

The pharmacokinetics of enasidenib do not appear to be affected substantially by age (19-100 years), gender, race, body weight (39-136 kg), or body surface area.

USES: This medication is used to treat a certain type of blood cell cancer (acute myeloid leukemia-AML). Enasidenib works by helping your bone marrow grow normal blood cells so you will need fewer blood transfusions. This drug has been withdrawn from the Canadian market due to problems with effectiveness.

Generic name: enasidenib mesylate
Pronunciation: (EN-a-SID-a-nib)

The following indications are listed for Idhifa:

• Acute Myeloid Leukemia With Isocitrate Dehydrogenase-2 (Idh2) Mutation

Also known as: Idh2 Mutated Aml, Idh2 Mutation-Positive Acute Myeloid Leukemia.

No ICD codes are available for this drug.