Ivosidenib is an oral inhibitor that targets isocitrate dehydrogenase 1 (IDH1) mutations. It was approved by the FDA in 2018 for the treatment of relapsed or refractory acute myeloid leukemia (AML) in patients harboring IDH1 mutations.

How Effective is Ivosidenib?

1. Key Study Data

(1) Complete Remission (CR) Rate: 24.7% (43/174), with a median duration of remission of 10.1 months.

(2) Complete Remission with Partial Hematologic Recovery (CRh): 8% (14/174), with a median duration of 3.6 months.

(3) Composite Remission Rate (CR + CRh): 32.8% (57/174), with a median duration of 8.2 months.

(4) Transfusion Independence: 37.3% of patients who were transfusion-dependent at baseline converted to transfusion independence.

2. Eligible Population

IDH1 mutations (e.g., R132H/C) must be confirmed using an FDA-approved test (such as the Abbott RealTime IDH1 Assay). The recommended dosage is 500mg once daily, administered continuously until disease progression or the development of intolerable toxicity.

Pharmacological Effects of Ivosidenib

1. Targeted Inhibition of IDH1 Mutations

(1) Ivosidenib selectively inhibits mutant IDH1 enzymes (e.g., R132H/C), blocking the production of the oncogenic metabolite 2-hydroxyglutarate (2-HG), thereby promoting the differentiation of leukemia cells.

(2) In vitro experiments have shown that its potency in inhibiting mutant IDH1 is significantly higher than that in inhibiting wild-type IDH1.

2. Multiple Biological Effects

(1) Metabolic Regulation: Reduces the levels of 2-HG in plasma and bone marrow by more than 90%.

(2) Differentiation Induction: Promotes the maturation of myeloid cells and reduces the proportion of blast cells.

(3) Cardiac Electrophysiological Impact: At steady-state plasma concentrations, it can prolong the QTc interval by approximately 16.1 milliseconds.

Pharmacokinetic Properties of Ivosidenib

1. Absorption and Distribution

(1) Absorption: The time to reach peak concentration (Tmax) is approximately 3 hours. A high-fat meal can increase the maximum plasma concentration (Cmax) by 98%.

(2) Distribution: The apparent volume of distribution is 234L, and the plasma protein binding rate ranges from 92% to 96%.

2. Metabolism and Excretion

(1) Metabolism: It is mainly metabolized by CYP3A4, with minor metabolic pathways including N-dealkylation and hydrolysis.

(2) Excretion: 77% of the drug is excreted via feces (67% as the parent drug), and 17% via urine (10% as the parent drug).

(3) Half-life: The half-life is 93 hours, and steady-state concentrations are reached after 14 days of continuous administration.

3. Drug Interactions

(1) CYP3A4 Inhibitors: Strong inhibitors (e.g., itraconazole) increase the area under the concentration-time curve (AUC) to 269%, requiring a dosage reduction to 250mg per day.

(2) CYP3A4 Inducers: Concomitant use should be avoided (e.g., rifampicin can reduce drug exposure by 33%).

(3) QTc-Prolonging Drugs: Concomitant use should be avoided, or enhanced cardiac monitoring should be implemented if co-administration is necessary.