ivosidenib 在 IDH1 突变的晚期血液系统恶性肿瘤患者中的临床药代动力学和药效学。
Clinical pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation.
机构信息
Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
出版信息
Cancer Chemother Pharmacol. 2020 May;85(5):959-968. doi: 10.1007/s00280-020-04064-6. Epub 2020 Apr 15.
PURPOSE
Isocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study (ClinicalTrials.gov NCT02074839).
METHODS
Patients received single and multiple oral doses of ivosidenib from 100 mg twice daily to 1200 mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4β-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity.
RESULTS
Ivosidenib was rapidly absorbed and slowly eliminated (half-life 72-138 h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4β-hydroxycholesterol/cholesterol ratios of 119-168% at 500-mg QD ivosidenib.
CONCLUSIONS
Ivosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov NCT02074839.
目的
异柠檬酸脱氢酶（IDH）突变导致致癌代谢物 2-羟戊二酸（2-HG）的形成，该物质在几种实体瘤和液体瘤中升高。ivosidenib（AG-120）是一种针对突变 IDH1 蛋白的靶向、有效、口服抑制剂。我们在一项 I 期研究（ClinicalTrials.gov NCT02074839）中描述了患有 IDH1 突变的晚期血液系统恶性肿瘤患者接受ivosidenib 单药和多药治疗的详细药代动力学和药效学。
方法
患者接受ivosidenib 单剂量和多剂量治疗，剂量范围为每日两次 100mg 至每日一次 1200mg（QD），连续 28 天给药。定期评估血浆中ivosidenib 和 2-HG 的浓度，以及骨髓中 2-HG 的浓度。评估血浆 4β-羟胆固醇/胆固醇比值作为 CYP3A 活性的标志物。
结果
ivosidenib 单剂量和多剂量给药后迅速吸收，缓慢消除（半衰期 72-138 小时）。ivosidenib 表现出剂量和时间依赖性药代动力学特征，暴露量与剂量不成比例地增加，清除率随剂量增加而增加。接受 500mg QD ivosidenib 的大多数患者的血浆 2-HG 浓度最大且持续抑制，接近健康受试者的浓度。轻度或中度肾功能损害、轻度肝功能损害、年龄、体重、性别、种族、或合用弱 CYP3A4 抑制剂或诱导剂对ivosidenib 的药代动力学无影响。中效至强效 CYP3A4 抑制剂降低了 ivosidenib 的清除率。ivosidenib 还诱导了 CYP3A 酶的活性，在 500mg QD ivosidenib 时，4β-羟胆固醇/胆固醇比值增加 119-168%。
结论
ivosidenib 500mg QD 在患有 IDH1 突变的晚期血液系统恶性肿瘤患者中具有良好的药代动力学和药效学特征。
临床试验注册
ClinicalTrials.gov NCT02074839。
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