Medical Information

Enasidenib, as an IDH2 mutation inhibitor, exerts anti leukemia effects by blocking the production of carcinogenic metabolite 2-HG. Its efficacy is related to the mutation subtype, and attention should be paid to the risk of interaction with drugs such as CYP3A4 modulators. The following provides a detailed explanation from three aspects: mechanism of action, therapeutic effect, and drug interactions.

1. Mechanism of action

(1) Targeted inhibition

Selective inhibition of mutant IDH2 enzyme, blocking the conversion of α - ketoglutarate to carcinogenic metabolite 2-hydroxyglutarate (2-HG), restores normal differentiation ability of hematopoietic cells.

(2) Metabolic intervention

By competitively occupying the mutated IDH2 active center and blocking the conversion of α - ketoglutarate to 2-hydroxyglutarate (2-HG), the level of 2-HG in tumor cells is reduced by over 90%.

(3) Epigenetic regulation

The clearance of 2-HG restores histone demethylase function, corrects abnormal DNA hypermethylation status, and relieves hematopoietic stem cell differentiation blockade.

2 therapeutic effects

(1) Single drug efficacy

In relapsed/refractory AML, the complete remission rate of IDH2R140 mutation patients is 38%, with a median remission duration of 5.6 months; The remission rate of R172 mutation patients is 15%, but the duration is up to 10.9 months.

(2) Combination therapy

Combined use with azacitidine increased the complete remission rate to 44% and extended the median overall survival to 22 months, significantly better than monotherapy.

3 drug interactions

(1) CYP3A4 regulator

Highly effective CYP3A4 inhibitors (such as ketoconazole) can increase the AUC of amlodipine by 2.7 times, requiring a 50% reduction in dosage; Strong inducers (such as rifampicin) can reduce drug exposure and should be avoided in combination.

(2) Sensitive substrate drugs

May increase the concentration of narrow therapeutic window drugs (such as midazolam) metabolized by CYP3A4. Adverse reactions should be monitored when used in combination, and the dosage should be adjusted if necessary.

(3) Gastric acid regulator

Proton pump inhibitors can reduce the Cmax of amlodipine by 45%. It is recommended to interval the administration of H2 receptor antagonists or antacids by more than 2 hours.