Agios Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
Current address: Servier Pharmaceuticals LLC, Boston, Massachusetts, USA.
Clin Pharmacol Drug Dev. 2022 Apr;11(4):429-441. doi: 10.1002/cpdd.1067. Epub 2022 Feb 14.
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 mIDH1 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 mIDH1/2 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.
突变的异柠檬酸脱氢酶 1/2（mIDH1/2）蛋白催化产生致癌代谢物 D-2-羟戊二酸（2-HG）。Ivosidenib 和enasidenib 分别是 mIDH1 和 mIDH2 的口服抑制剂。一项开放标签的 1 期研究正在评估ivosidenib 或 enasidenib 联合强化诱导和巩固化疗在新诊断的 mIDH1/2 急性髓系白血病（AML；NCT02632708）成人患者中的安全性和疗效。在这一人群中，我们对ivosidenib 和 enasidenib 的药代动力学（PK）、药效学（PD）和 PK/PD 关系进行了描述。患者接受连续口服ivosidenib 500mg 每日 1 次或enasidenib 100mg 每日 1 次联合化疗。连续采集血样以测量 mIDH 抑制剂的浓度。2-HG 浓度同时在血浆和骨髓抽吸物中进行测量。共采集了 60 例接受ivosidenib 治疗和 91 例接受enasidenib 治疗的患者样本。对于这两种药物，稳态时的暴露量均高于单次剂量，ivosidenib 和 enasidenib 的平均蓄积比（基于 0 至 24 小时的血浆浓度-时间曲线下面积）分别为 2.35 和 8.25。基线时的平均血浆 2-HG 浓度升高。多次ivosidenib 或enasidenib 给药后，平均谷值血浆 2-HG 浓度降至健康个体水平，并随着持续给药而维持。骨髓 2-HG 浓度相应降低。在新诊断的 mIDH1/2 AML 患者中，ivosidenib 和 enasidenib 联合强化化疗时，PK/PD 特征与单药治疗时相似。这些发现支持ivosidenib 或 enasidenib 联合强化化疗用于治疗新诊断的 mIDH1/2 AML 患者。
