萨妥珠单抗戈维替康在转移性三阴性乳腺癌和其他实体瘤患者中的群体药代动力学研究

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Abhishek G. Sathe, Indrajeet Singh, Pratap Singh, Paul M. Diderichsen, Xiaohui Wang, Peter Chang, Atiya Taqui, See Phan, Sandhya Girish, Ahmed A. Othman
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引用次数: 0

摘要

背景与目的Sacituzumab govitecan(SG)是一种抗体-药物共轭物,由对Trop-2具有亲和力的抗体通过可水解连接体与SN-38偶联而成。SG被批准用于既往接受过两种或两种以上化疗(至少一种是转移性化疗)的转移性三阴性乳腺癌(mTNBC)患者,以及经预处理的激素受体阳性(HR+)/人表皮生长因子受体2阴性(HER2-)的转移性乳腺癌患者。方法在这些分析中,利用两项大型临床试验(NCT01631552;ASCENT,NCT02574455)中 529 例 mTNBC 或其他实体瘤患者的数据,对 SG、游离 SN-38 和总抗体 (tAB) 的药代动力学进行了表征。使用非线性混合效应模型构建了三个群体药代动力学模型;评估了与临床相关的协变量,以评估其对暴露的影响。SG 和 tAB 的模型是独立建立的,而游离 SN-38 则是通过 SG 的一阶释放过程依次产生的。结果三种分析物的药代动力学均由一个两室模型来描述,该模型具有基于体重的估计清除率和体积缩放指数。SG 和 tAB 的清除率和稳态分布容积的典型参数估计分别为 0.133 L/h 和 3.68 L,0.0164 L/h 和 4.26 L。轻度至中度肾功能损害、轻度肝功能损害、年龄、性别、基线白蛋白水平、肿瘤类型、UGT1A1 基因型或 Trop-2 表达对三种分析物中任何一种的暴露量都没有临床相关影响。结论这些分析支持已批准的 SG 给药方案,即在 21 天周期的第 1 天和第 8 天静脉注射 10 mg/kg,并且没有发现需要根据评估的协变量或疾病特征进行剂量调整。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Population Pharmacokinetics of Sacituzumab Govitecan in Patients with Metastatic Triple-Negative Breast Cancer and Other Solid Tumors

Population Pharmacokinetics of Sacituzumab Govitecan in Patients with Metastatic Triple-Negative Breast Cancer and Other Solid Tumors

Background and Objective

Sacituzumab govitecan (SG) is an antibody–drug conjugate composed of an antibody with affinity for Trop-2 coupled to SN-38 via hydrolyzable linker. SG is approved for patients with metastatic triple-negative breast cancer (mTNBC) who have received two or more prior chemotherapies (at least one in a metastatic setting) and for patients with pretreated hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2–) metastatic breast cancer.

Methods

In these analyses, the pharmacokinetics of SG, free SN-38, and total antibody (tAB) were characterized using data from 529 patients with mTNBC or other solid tumors across two large clinical trials (NCT01631552; ASCENT, NCT02574455). Three population pharmacokinetic models were constructed using non-linear mixed-effects modeling; clinically relevant covariates were evaluated to assess their impact on exposure. Models for SG and tAB were developed independently whereas free SN-38 was sequentially generated via a first-order release process from SG.

Results

Pharmacokinetics of the three analytes were each described by a two-compartment model with estimated body weight-based scaling exponents for clearance and volume. Typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/h and 3.68 L for SG and 0.0164 L/h and 4.26 L for tAB, respectively. Mild-to-moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, tumor type, UGT1A1 genotype, or Trop-2 expression did not have a clinically relevant impact on exposure for any of the three analytes.

Conclusions

These analyses support the approved SG dosing regimen of 10 mg/kg as intravenous infusion on days 1 and 8 of 21-day cycles and did not identify a need for dose adjustment based on evaluated covariates or disease characteristics.

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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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