来那度胺过度暴露引起的血液学毒性的临床管理:基于模型的中国肾功能不全人群精确给药。

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Yi Ma, Zaiwei Song, Hao Bing, Huan He, Libo Zhao, Rongsheng Zhao
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引用次数: 0

摘要

来那度胺的剂量依赖性血液学毒性先前已有报道,因此,临床需要剂量个体化来管理毒性。本研究旨在探讨中国不同程度肾功能b细胞恶性肿瘤患者的最佳个体化给药方案,推动来那度胺过度暴露血液学毒性的临床管理。从一项多中心前瞻性研究中获得了97名中国多发性骨髓瘤(MM)和b细胞非霍奇金淋巴瘤(NHL)患者的164个血浆来那度胺浓度。采用非线性混合效应模型建立来那度胺的群体药代动力学模型。通过蒙特卡罗模拟,为不同程度肾功能的患者推荐模型知情精确给药(MIPD)。一阶消除的单室模型最好地描述了来那度胺的药代动力学。来那度胺的人群典型值为:吸收率常数(Ka)为8.34 h-1,表观分布容积(V/F)为37.4 L,表观清除率(CL/F)为7.4 L/h。肌酐清除率(CCr)被确定为CL/F的主要协变量,而其他人口统计学或临床特征对模型没有显著影响。当给予相同剂量时,中国患者在所有剂量方案中都比主要的非亚洲人群暴露更高,特别是在严重肾损害(CCr)患者中
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Push Forward Clinical Management of Hematological Toxicity due to Lenalidomide Overexposure: Model-Informed Precision Dosing for Chinese Population With Renal Insufficiency.

Dose-dependent hematological toxicity of lenalidomide has been reported previously, and thus, there is a clinical need for dose individualization to manage toxicities. The objectives of this study were to explore optimal individualized dosing regimens for Chinese B-cell malignancies patients with varying degrees of renal function, and to push forward clinical management of hematological toxicity due to lenalidomide overexposure. A total of 164 plasma concentrations of lenalidomide were obtained from 97 Chinese patients with multiple myeloma (MM) and B-cell non-Hodgkin lymphoma (NHL) from a multicenter prospective study. A population pharmacokinetic (PopPK) model for lenalidomide was developed by nonlinear mixed effect modeling. A Monte Carlo simulation was conducted to recommend model-informed precision dosing (MIPD) for patients with varying degrees of renal function. A one-compartment model with first-order elimination best described the pharmacokinetics of lenalidomide. The population typical values of lenalidomide were as follows: absorption rate constant (Ka) of 8.34 h-1, apparent volume of distribution (V/F) of 37.4 L, and apparent clearance (CL/F) of 7.4 L/h. Creatinine clearance (CCr) was identified as a major covariate for CL/F, whereas other demographics or clinical characteristics had no significant effect on the model. When given the identical dose, Chinese patients exhibited a higher exposure than the predominantly non-Asian population at all dosage regimens, especially in patients with severe renal damage (CCr < 30 mL/min). For Chinese patients with CCr of 15-30 mL/min who do not require dialysis usually, compared to the dosing regimen of 15 mg every other day recommended by drug instructions, there exists a relatively lower risk of hematotoxicity when administered with 5 or 10 mg/day. For Chinese patients with CCr < 15 mL/min requiring dialysis, there was still a certain level of hematotoxicity risk associated with the dosing regimen of 5 mg/day recommended by drug instructions. The PopPK Model-based simulation suggests that Chinese patients may exhibit a higher exposure than the predominantly non-Asian population. For patients with severely impaired renal function, compared to dose adjustment in accordance with drug instructions, an individualized dosage strategy based on therapeutic drug monitoring (TDM) and MIPD would be preferable from a safety perspective.

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来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
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