将单克隆抗体基于平台生理学的药代动力学模型扩展到不同的临床前物种:猫、羊和狗。

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2023-11-10 DOI:10.1007/s10928-023-09893-5
Hsien-Wei Huang, Shengjia Wu, Ekram A Chowdhury, Dhaval K Shah
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引用次数: 0

摘要

单克隆抗体(mAbs)正在成为兽医学中的一种重要治疗选择,了解mAbs在高级动物物种中的药代动力学(PK)对人类药物开发也很重要。为了更好地了解单克隆抗体在这些动物中的PK,我们扩展了一个基于平台生理学的药代动力学(PBPK)模型,以表征单克隆抗体在三种不同的临床前物种中的分布:猫、羊和狗。我们从文献中获得了单克隆抗体的PK数据和三种不同物种的生理参数。通过固定生理参数并仅估计与单克隆抗体与新生儿Fc受体结合相关的参数,我们能够很好地描述猫静脉(IV)或皮下给药、绵羊静脉给药和狗静脉给药后单克隆抗体的PK。本文提出的平台PBPK模型为预测狗、猫和羊的单克隆抗体血浆PK提供了一个定量工具。该模型还可以预测作用位点可能所在的不同组织中的mAb PK。因此,本文提出的mAb-PBPK模型可以促进用于兽医和人类医学的mAb的发现、开发和临床前到临床的转化。该模型也可以在未来进行修改,以解释某些器官的更详细的分区、动物的不同病理生理学以及靶向介导的药物处置。
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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Expansion of platform physiologically-based pharmacokinetic model for monoclonal antibodies towards different preclinical species: cats, sheep, and dogs.

Monoclonal antibodies (mAbs) are becoming an important therapeutic option in veterinary medicine, and understanding the pharmacokinetic (PK) of mAbs in higher-order animal species is also important for human drug development. To better understand the PK of mAbs in these animals, here we have expanded a platform physiological-based pharmacokinetic (PBPK) model to characterize the disposition of mAbs in three different preclinical species: cats, sheep, and dogs. We obtained PK data for mAbs and physiological parameters for the three different species from the literature. We were able to describe the PK of mAbs following intravenous (IV) or subcutaneous administration in cats, IV administration in sheep, and IV administration dogs reasonably well by fixing the physiological parameters and just estimating the parameters related to the binding of mAbs to the neonatal Fc receptor. The platform PBPK model presented here provides a quantitative tool to predict the plasma PK of mAbs in dogs, cats, and sheep. The model can also predict mAb PK in different tissues where the site of action might be located. As such, the mAb PBPK model presented here can facilitate the discovery, development, and preclinical-to-clinical translation of mAbs for veterinary and human medicine. The model can also be modified in the future to account for more detailed compartments for certain organs, different pathophysiology in the animals, and target-mediated drug disposition.

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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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