...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Translational Model-Based Strategy to Guide the Choice of Clinical Doses for Antibody-Drug Conjugates
【24h】

Translational Model-Based Strategy to Guide the Choice of Clinical Doses for Antibody-Drug Conjugates

机译：基于转化模型的策略指导抗体 - 药物缀合物的临床剂量选择

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

This work proposes a model-based approach to help select the phase 1 dosing regimen for the antibody-drug conjugate (ADC) SAR408701 leveraging the available data for 2 other ADCs of the same construct: SAR3419 and SAR566658. First, monkey and human pharmacokinetic (PK) data of SAR566658 and SAR3419 were used to establish the appropriate allometric approach to be applied to SAR408701 monkey PK data. Second, a population pharmacokinetics-pharmacodynamics (PK-PD) model was developed to describe tumor volume evolution following SAR408701 injection in mice. Third, allometric approaches identified for SAR566658 and SAR3419 were applied to SAR408701 monkey PK data to predict the human PK profile. Both SAR566658 and SAR3419 human and monkey PK were best described by a 2-compartment linear model. The relative difference was less than 10% between predicted and observed clearance using allometric exponents of 0.75 and 1, respectively. Tumor volume evolution following SAR408701 injection was best described by a full Simeoni model with a plasma concentration threshold of 4.6g/mL for eradication in mice. Both allometric exponents were used to predict SAR408701 PK in human from PK in monkey and to identify the potential effective dosing regimens. This translational strategy may be a valuable tool to design future clinical studies for ADCs, to support selection of the most appropriate dosing regimen, and to estimate the minimal dose required to assure antitumor activity, according to the schedule used.
机译：该工作提出了一种基于模型的方法，以帮助选择用于抗体 - 药物缀合物（ADC）SAR408701的第1阶段剂量方案，用于利用相同构建体的其他2个ADC的可用数据：SAR3419和SAR566658。首先，使用SAR566658和SAR3419的猴子和人体药代动力学（PK）数据来建立适用于SAR408701猴子PK数据的适当种类方法。其次，开发了一种人口药代动力学药物动力学（PK-PD）模型以描述在小鼠中的SAR408701注射之后描述肿瘤体积演化。第三，将针对SAR566658和SAR3419识别的各种方法应用于SAR408701猴PK数据以预测人类PK型材。 SAR566658和SAR3419人和猴子PK都是由2室线性模型描述的。在使用0.75和1的各种指数分别在预测和观察到的间隙之间的相对差异小于10％。在SAR408701注射之后的肿瘤体积演化是由血浆浓度阈值的全长模型最佳地描述，该血浆浓度阈值为4.6g / mL，用于在小鼠中根除。两种同种异体指数都用于预测来自猴子中的PK的人中的SAR408701 PK，并鉴定潜在的有效剂量方案。这种转化策略可能是设计未来ADC的临床研究的有价值的工具，以支持选择最合适的给药方案，并根据所用的时间表来估计确保抗肿瘤活性所需的最小剂量。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号