Ivosidenib (Mechanism of Action)

In this article, we will discuss Ivosidenib (Mechanism of Action). So, let’s get started.

Mechanism of Action

Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. Susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of ivosidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations are R132H and R132C substitutions. Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. Inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2­ HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex-vivo, reduced blast counts, and increased percentages of mature myeloid cells.

Pharmacodynamics

Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies to levels similar to those observed at baseline in healthy subjects. In bone marrow, 2-HG concentrations were reduced by >90%.

Cardiac Electrophysiology

A concentration-dependent QTc interval prolongation of approximately 16.1 msec (90% CI: 13.3, 18.9) was observed at the steady-state Cmax following a 500 mg daily dose based on an analysis of 171 patients with an IDH1 mutation, including 136 patients with relapsed or refractory AML, who received TIBSOVO 500 mg daily. Co-administration with moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline.