Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment.

IF 3.1 Q2 PHARMACOLOGY & PHARMACY
Clinical Pharmacology : Advances and Applications Pub Date : 2019-02-15 eCollection Date: 2019-01-01 DOI:10.2147/CPAA.S192687
Yan Li, Jamie N Connarn, Jian Chen, Zeen Tong, Maria Palmisano, Simon Zhou
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引用次数: 8

Abstract

Background: Enasidenib (IDHIFA®, AG-221) is a first-in-class, targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. This was a Phase I/II study evaluating safety, efficacy, and pharmacokinetics/pharmacodynamics (PK/PD) of orally administered enasidenib in subjects with advanced hematologic malignancies with an IDH2 mutation.

Methods: Blood samples for PK and PD assessment were collected. A semi-mechanistic nonlinear mixed effect PK/PD model was successfully developed to characterize enasidenib plasma PK and to assess enasidenib-induced CYP3A activity.

Results: The PK model showed that enasidenib plasma concentrations were adequately described by a one-compartment model with first-order absorption and elimination; the PD model showed a high capacity to induce CYP3A (Emax=7.36) and a high enasidenib plasma concentration to produce half of maximum CYP3A induction (EC50 =31,400 ng/mL). Monte Carlo simulations based on the final PK/PD model showed that at 100 mg once daily dose there was significant drug accumulation and a maximum of three-fold CYP3A induction after multiple doses. Although the EC50 value for CYP3A induction by enasidenib is high, CYP3A induction was observed due to significant drug accumulation.

Conclusion: CYP3A induction following enasidenib dosing should be considered when prescribing concomitant medication metabolized via this pathway.

Abstract Image

Abstract Image

Abstract Image

enasidenib治疗期间内源性CYP3A诱导标记物4β-羟胆固醇的建模和模拟。
背景:Enasidenib (IDHIFA®,AG-221)是一种一流的IDH2突变蛋白靶向抑制剂,用于治疗复发或难治性急性髓系白血病。这是一项I/II期研究,评估口服enasidenib治疗伴有IDH2突变的晚期血液恶性肿瘤患者的安全性、有效性和药代动力学/药效学(PK/PD)。方法:采集血样进行PK和PD评估。成功建立了半机制非线性混合效应PK/PD模型,以表征enasidenib血浆PK并评估enasidenib诱导的CYP3A活性。结果:药代动力学模型显示,enasidenib的血药浓度可以用一阶吸收消除的单室模型来描述;PD模型具有较高的CYP3A诱导能力(Emax=7.36)和较高的enasidenib血药浓度(EC50 =31,400 ng/mL),达到最大CYP3A诱导能力的一半。基于最终PK/PD模型的蒙特卡罗模拟显示,在100mg每日一次剂量下,存在显著的药物积累,多次给药后CYP3A诱导量最高可达3倍。虽然enasidenib诱导CYP3A的EC50值很高,但由于药物积累明显,观察到CYP3A的诱导作用。结论:在处方通过该途径代谢的合用药物时,应考虑给药后的CYP3A诱导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
4.60
自引率
0.00%
发文量
14
审稿时长
16 weeks
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