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Isocitrate dehydrogenase-1 (IDH1) inhibitor46
IDH1 mutated myeloid leukemia†
Ivosidenib is the first-in-class isocitrate dehydrogenase-1 (IDH1) inhibitor. It is approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation (i.e., R132C, R132H, R132G, R132S and R132L)89 as detected by the Abbott RealTimeTM IDH1 Assay (Abbott Laboratories).34 Ivosidenib has been designated as an orphan drug for AML since 2015, for cholangiocarcinoma since 2017, and for glioma since 2018.21 Per the approved labeling, susceptible IDH1 mutations are those that result in a new ability of the enzyme to catalyze the reduction of alpha-ketoglutarate (αKG) to the oncometabolite 2-hydroxyglutarate (2HG).90-93 2HG is an inhibitor of αKG-dependent dioxygenases, which include several histone demethylases.91-93 2HG accumulation in IDH1-expressing cancer cells promotes hypermethylation of histones, suppression of cell-differentiation genes, and disruption of hematopoietic cell differentiation.91,93 Administration of ivosidenib is demonstrated to reduce 2-HG levels in plasma and bone marrow.93 By reducing the abnormal production of 2HG, ivosidenib is thought to reduce the inhibition of histone demethylases and promote normalization of cell methylation conditions.91,93 In patients with AML, administration of ivosidenib reduces blast counts, increases mature myeloid cells, and leads to cancer regression.47,91
The adverse effects of particular importance associated with ivosidenib therapy include differentiation syndrome (10%), leukocytosis (10%), prolonged QTc interval (7%), and Guillain-Barré syndrome (<1%).47 At least one case of progressive multifocal leukoencephalopathy has been reported.47 Assessments of blood counts, blood chemistries, blood creatine phosphokinase, and electrocardiograms are necessary to gauge the clinical response to ivosidenib and guide toxicity-related dose modifications (refer to the product labeling for details).47 Ivosidenib is given orally at a dose of 500 mg once daily until disease progression or unacceptable toxicity.89 Treatment for 6 months may be required for a clinical response.47 Ivosidenib has a half-life of 93 hours and reaches steady-state within 14 days of therapy initiation.89 It is primarily metabolized by CYP3A4 with elimination mainly in the feces.47 Ivosidenib is an inducer of CYP3A4 and may induce CYPs 2B6, 2C8, and 2C9.47 Dose modifications are necessary if ivosidenib must be co-administered with a strong CYP3A4 inhibitor.47 Ivosidenib also is a substrate for and inhibitor of P-glycoprotein and an inhibitor of OAT3.47 The chemical structure of ivosidenib is shown in Figure P1-4.
FDA approval of ivosidenib for AML was made on the basis of results from an open-label, single-arm, multicenter clinical trial of 174 adult patients with relapsed or refractory AML (NCT02074839).47,94 Complete remission was achieved in 43 patients (24.7%) with a median duration just over 10 months.47 Complete remission or a complete remission with a partial hematologic recovery that lasted for a median of just over 8 months was achieved by 32.8% of patients.47
Chemical structure of ivosidenib95 (PubChem CID: 71657455; IUPAC Name: (2S})-N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide).
Chapter 67. Pathway-Targeted Therapies: Monoclonal Antibodies, Protein Kinase Inhibitors, and Various Small Molecules
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals