期刊
CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT
卷 11, 期 4, 页码 429-441出版社
WILEY
DOI: 10.1002/cpdd.1067
关键词
AML; enasidenib; isocitrate dehydrogenase; ivosidenib; PK/PD
资金
- Agios Pharmaceuticals, Inc.
- Bristol-Myers Squibb
- Agios Pharmaceuticals, Inc
- Servier Pharmaceuticals LLC.
In this study, the pharmacokinetics, pharmacodynamics, and PK/PD relationships of ivosidenib and enasidenib in newly diagnosed nnIDH1/2 AML patients were characterized. The results showed that the profiles of ivosidenib and enasidenib in combination with intensive chemotherapy were similar to those when they are given as single agents. These findings support the dosing of ivosidenib or enasidenib in combination with intensive chemotherapy for the treatment of newly diagnosed mIDH1/2 AML patients.
Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) proteins catalyze production of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib and enasidenib are oral inhibitors of nnIDH1 and mIDH2, respectively. An open-label phase 1 study is evaluating the safety and efficacy of ivosidenib or enasidenib combined with intensive induction and consolidation chemotherapy in adult patients with newly diagnosed nnIDH1/2 acute myeloid leukemia (AML; NCT02632708). In this population, we characterized the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships for ivosidenib and enasidenib. Patients received continuous oral ivosidenib 500 mg once daily or enasidenib 100 mg once daily combined with chemotherapy. Serial blood samples were collected for measurement of the concentrations of the mIDH inhibitors. 2-HG concentrations were measured in both plasma and bone marrow aspirates. Samples were collected from 60 patients receiving ivosidenib and 91 receiving enasidenib. For both drugs, exposures at steady state were higher than after single doses, with mean accumulation ratios (based on area under the plasma concentration-time curve from time 0 to 24 hours) of 2.35 and 8.25 for ivosidenib and enasidenib, respectively. Mean plasma 2-HG concentrations were elevated at baseline. After multiple ivosidenib or enasidenib doses, mean trough plasma 2-HG concentrations decreased to levels observed in healthy individuals and were maintained with continued dosing. There was a corresponding reduction in bone marrow 2-HG concentrations. When combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML, ivosidenib and enasidenib demonstrated PK/PD profiles similar to those when they are given as single agents. These findings support the dosing of ivosidenib or enasidenib in combination with intensive chemotherapy for the treatment of patients with newly diagnosed mIDH1/2 AML.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据