曲妥珠单抗-药物共轭物(T-DM1)临床前药物代谢动力学研究及人体药物代谢动力学预测

钟华，谢东，朱建伟

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主办：上海医药工业研究院
　　　中国药学会
　　　中国化学制药工业协会
ISSN 1001-8255   CN 31-1243/R   ZYGZEA
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中国医药工业杂志
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中国医药工业杂志 ›› 2020, Vol. 51 ›› Issue (02) : 239-248. DOI: 10.16522/j.cnki.cjph.2020.02.015
研究论文 Paper

曲妥珠单抗-药物共轭物(T-DM1)临床前药物代谢动力学研究及人体药物代谢动力学预测

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Pre-clinical Pharmacokinetic Research and Human Pharmacokinetic Projection of Trastuzumab Emtansine(T-DM1)

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摘要

本试验通过临床前药物代谢动力学(PK) 和毒理学研究结果，对曲妥珠单抗- 药物共轭物(T-DM1) 的人体PK 特性进行了预测，并探讨了目前广泛采用的预测方法的不足和可能的解决途径。本试验首先进行了动物试验，包括大鼠急性毒性试验和食蟹猴PK 试验，通过试验获得了T-DM1 的总抗体、偶联抗体和游离小分子药物emtansine(DM1) 的PK 参数，随后基于这些参数，使用异速增长模型和种属- 时间不变法，对总抗体和偶联抗体的人体PK 特性进行了预测。此外，通过参考近年的一些相关研究，探讨了如何基于动物生理药动学(PBPK) 模型，更科学地预测抗体偶联药物中小分子药物的人体PK 和分布特性。

Abstract

The objective of this article is to predict human pharmacokinetic(PK) parameters of trastuzumab emtansine(T-DM1) by using the preclinical PK data, and discuss how to overcome the disadvantages of current methods of human PK projection. The pre-clinical studies we conducted including rat acute toxicity and single dose cynomolgus monkey PK study. Thereafter, for total antibody and antibody-drug conjugates(ADCs), we predicted human PK data by using allometric scaling and species-invariant time method that based on the results of monkey PK study. We summarized the opinions of some recent researches related to human PK projection of ADCs by using physiologically based pharmacokinetic(PBPK) model. Meanwhile, based on the previous studies, we also discussed how to build an appropriate model for ADCs, so that human PK and disposition of the small molecular drug could be well predicted.

关键词

临床前药物代谢动力学 / 人体药物代谢动学预测 / 生理药动学(PBPK) 模型 / 曲妥珠单抗- 药物共轭物(T-DM1)

Key words

pre-clinical pharmacokinetics / human pharmacokinetic projection / physiologically based pharmacokinetic(PBPK) model / trastuzumab emtansine(T-DM1)

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钟华，谢东，朱建伟. 曲妥珠单抗-药物共轭物(T-DM1)临床前药物代谢动力学研究及人体药物代谢动力学预测. 中国医药工业杂志. 2020, 51(02): 239-248 https://doi.org/10.16522/j.cnki.cjph.2020.02.015
ZHONG Hua, XIE Dong, ZHU Jianwei. Pre-clinical Pharmacokinetic Research and Human Pharmacokinetic Projection of Trastuzumab Emtansine(T-DM1). Chinese Journal of Pharmaceuticals. 2020, 51(02): 239-248 https://doi.org/10.16522/j.cnki.cjph.2020.02.015

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