Population Pharmacokinetics of Valemetostat and Exposure-Response Analyses of Efficacy and Safety in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma.

IF 2.3 4区 医学
Hiroyuki Inoue, Xiaoning Wang, Ramon Garcia, Brian Reilly, Masaya Tachibana, YoungJun Yoo, Yvonne Lau, Yang Chen
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引用次数: 0

Abstract

Valemetostat is a dual inhibitor of EZH2/1 approved in Japan for the treatment of relapsed/refractory (R/R) adult T-cell lymphoma/leukemia (ATLL) and R/R peripheral T-cell lymphoma (PTCL). It is administered orally once daily (QD) at 200 mg. Here, we present comprehensive population pharmacokinetic (PPK) and exposure-response (ER) analyses of valemetostat. The PPK model included data from six clinical trials in patients with non-Hodgkin lymphoma, including ATLL/PTCL, or healthy participants. ER efficacy analyses were based on data from one phase 2 clinical trial in patients with PTCL; ER safety analyses used data from three trials in patients with ATLL or PTCL. Valemetostat unbound average concentration up to event was used as the exposure metric. ER analyses included overall response rates for efficacy and six safety endpoints (any Grade ≥3 treatment-emergent adverse event [TEAE]; Grade ≥3 thrombocytopenia, anemia, and neutropenia; and dose reduction and interruption due to TEAEs). Valemetostat pharmacokinetics were well described by a three-compartment model, with a sequential linked zero-/first-order absorption, a saturable binding component in the central compartment, and linear elimination of unbound valemetostat from the central compartment. Alpha-1-acid glycoprotein was the only identified covariate significantly affecting total valemetostat exposure but had no impact on unbound exposure. The ER relationship on efficacy was not significant, and positive relationships were identified for multiple safety endpoints. Safety simulations across different doses suggested an acceptable safety profile for 200 mg QD. Overall, these analyses support the favorable benefit-risk profile of valemetostat at 200 mg QD in patients with R/R PTCL.

伐美他汀在复发/难治性外周t细胞淋巴瘤患者中的人群药代动力学及疗效和安全性暴露反应分析。
Valemetostat是EZH2/1的双重抑制剂,在日本被批准用于治疗复发/难治性(R/R)成人t细胞淋巴瘤/白血病(ATLL)和R/R外周t细胞淋巴瘤(PTCL)。每日口服一次(QD),剂量为200毫克。在这里,我们介绍了伐美他汀的综合人群药代动力学(PPK)和暴露反应(ER)分析。PPK模型包括来自非霍奇金淋巴瘤患者(包括ATLL/PTCL)或健康参与者的六项临床试验的数据。ER疗效分析基于一项PTCL患者2期临床试验的数据;ER安全性分析使用了atall或PTCL患者的三个试验数据。使用Valemetostat在事件发生前的未结合平均浓度作为暴露度量。ER分析包括疗效的总有效率和6个安全性终点(任何≥3级治疗不良事件[TEAE];≥3级血小板减少、贫血和中性粒细胞减少;TEAE导致的剂量减少和中断)。缬美托他的药代动力学由三室模型很好地描述,具有顺序链接的零/一阶吸收,中央室的饱和结合成分,以及从中央室线性消除未结合的缬美托他。α -1-酸性糖蛋白是唯一确定的协变量,显著影响缬美他汀总暴露量,但对未结合暴露量没有影响。ER与疗效的关系不显著,多个安全终点均存在正相关。不同剂量的安全性模拟表明,每日200毫克的安全性是可以接受的。总的来说,这些分析支持valemetostat在R/R PTCL患者中每日200mg的有利获益-风险概况。
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
Journal of Clinical Pharmacology
Journal of Clinical Pharmacology PHARMACOLOGY & PHARMACY-
自引率
3.40%
发文量
0
期刊介绍: The Journal of Clinical Pharmacology (JCP) is a Human Pharmacology journal designed to provide physicians, pharmacists, research scientists, regulatory scientists, drug developers and academic colleagues a forum to present research in all aspects of Clinical Pharmacology. This includes original research in pharmacokinetics, pharmacogenetics/pharmacogenomics, pharmacometrics, physiologic based pharmacokinetic modeling, drug interactions, therapeutic drug monitoring, regulatory sciences (including unique methods of data analysis), special population studies, drug development, pharmacovigilance, womens’ health, pediatric pharmacology, and pharmacodynamics. Additionally, JCP publishes review articles, commentaries and educational manuscripts. The Journal also serves as an instrument to disseminate Public Policy statements from the American College of Clinical Pharmacology.
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