Review of dose justifications for antibody-drug conjugate approvals from clinical pharmacology perspective: A focus on exposure-response analyses.

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL
Qianqian Hu, Lujing Wang, Yuqing Yang, Jong Bong Lee
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引用次数: 0

Abstract

Antibody-drug conjugates (ADCs) are revolutionizing cancer treatment by specific targeting of the cancer cells thereby improving the therapeutic window of the drugs. Nevertheless, they are not free from unwanted toxicities mainly resulting from non-specific targeting and release of the payload. Therefore, the dosing regimen must be optimized through integrated analysis of the risk-benefit profile, to maximize the therapeutic potential. Exposure-response (E-R) analysis is one of the most widely used tools for risk-benefit assessment and it plays a pivotal role in dose optimization of ADCs. However, compared to conventional E-R analysis, ADCs pose unique challenges since they feature properties of both small molecules and antibodies. In this article, we review the E-R analyses that have formed the key basis of dose justification for each of the 12 ADCs approved in the USA. We discuss the multiple analytes and exposure metrics that can be utilized for such analysis and their relevance for safety and efficacy of the treatment. For the endpoints used for the E-R analysis, we were able to uncover commonalities across different ADCs for both safety and efficacy. Additionally, we discuss dose optimization strategies for ADCs which are now a critical component in clinical development of oncology drugs.

从临床药理学角度审查抗体药物共轭物审批的剂量理由:重点关注暴露-反应分析。
抗体药物共轭物(ADCs)通过特异性靶向癌细胞从而改善药物的治疗窗口期,为癌症治疗带来了革命性的变化。然而,ADCs 也存在一些不必要的毒性,主要是由于非特异性靶向和有效载荷的释放。因此,必须通过对风险-效益概况的综合分析来优化给药方案,以最大限度地发挥治疗潜力。暴露-反应(E-R)分析是风险-效益评估中使用最广泛的工具之一,在 ADC 的剂量优化中起着举足轻重的作用。然而,与传统的 E-R 分析相比,ADC 具有小分子和抗体的双重特性,因此带来了独特的挑战。在这篇文章中,我们回顾了作为美国批准的 12 种 ADC 中每一种的剂量论证的重要依据的 E-R 分析。我们讨论了可用于此类分析的多种分析物和暴露指标,以及它们与治疗安全性和有效性的相关性。对于用于 E-R 分析的终点,我们能够发现不同 ADC 在安全性和有效性方面的共性。此外,我们还讨论了 ADC 的剂量优化策略,该策略现已成为肿瘤药物临床开发的重要组成部分。
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
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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