Translational PK/PD framework for antibody-drug conjugates to inform drug discovery and development.

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Xenobiotica Pub Date : 2024-08-01 Epub Date: 2024-09-27 DOI:10.1080/00498254.2024.2351044

Michael Z Liao, Douglas D Leipold, Shang-Chiung Chen, Zao Li, Amrita V Kamath, Chunze Li

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引用次数: 0

Abstract

ADCs represent a transformative class of medicine that combines the specificity of monoclonal antibodies with the potency of highly cytotoxic agents through linkers, aiming to enhance the therapeutic index of cytotoxic drugs. Given the complex molecular structures of ADCs, combining the molecular characteristics of small-molecule drugs and those of large-molecule biotherapeutics, there are several unique considerations when designing nonclinical-to-clinical PK/PD translation strategies.This complexity also demands a thorough understanding of the ADC's components - antibody, linker, and payload - to the overall toxicological, PK/PD, and efficacy profile. ADC development is a multidisciplinary endeavour requiring a strategic integration of nonclinical safety, pharmacology, and PK/PD modelling to translate from bench to bedside successfully.The ADC development underscores the necessity for a robust scientific foundation, leveraging advanced analytical and modelling tools to predict human responses and optimise therapeutic outcomes.This review aims to provide an ADC translational PK/PD framework by discussing unique aspects of ADC nonclinical to clinical PK translation, starting dose determination, and leveraging PK/PD modelling for human efficacious dose prediction and potential safety mitigation.

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抗体药物结合体的转化 PK/PD 框架，为药物发现和开发提供信息。

(171/200)ADCs是一类变革性药物，通过连接体将单克隆抗体的特异性与高细胞毒性药物的效力结合起来，旨在提高细胞毒性药物的治疗指数。由于 ADC 的分子结构复杂，兼具小分子药物和大分子生物治疗药物的分子特征，因此在设计非临床到临床的 PK/PD 转化策略时需要考虑一些独特的因素。这种复杂性还要求对 ADC 的组成成分--抗体、连接体和有效载荷--以及整体毒理学、PK/PD 和疗效特征有透彻的了解。ADC 的开发是一项多学科的工作，需要对非临床安全性、药理学和 PK/PD 建模进行战略性整合，才能成功地从实验室转化到临床。ADC 的开发凸显了强大科学基础的必要性，需要利用先进的分析和建模工具来预测人体反应并优化治疗效果。本综述旨在提供一个 ADC PK/PD 转化框架，讨论 ADC 非临床到临床 PK 转化、起始剂量确定以及利用 PK/PD 建模进行人体有效剂量预测和潜在安全性缓解的独特方面。

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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来源期刊

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

审稿时长

2 months

期刊介绍： Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology