PARP inhibitors: A review of the pharmacology, pharmacokinetics, and pharmacogenetics

IF 3 3区 医学 Q2 ONCOLOGY Seminars in oncology Pub Date : 2024-02-01 DOI:10.1053/j.seminoncol.2023.09.005
Yi Zeng , Oluwatobi Arisa , Cody J. Peer , Antonio Fojo , William D. Figg
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Abstract

PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors target PARP enzymes involved in DNA repair pathways and exhibit remarkable efficacy in cancers with genetic deficiencies in the homologous recombination pathway responsible for mending DNA double-strand breaks. While all PARP inhibitors demonstrate potent and selective inhibition of PARP1 and PARP2, the key enzymes involved in DNA repair, each agent within the class possesses unique pharmacological profiles distinguishing them from one another.

This review aims to comprehensively examine the properties of the entire PARP inhibitor class while emphasizing individual pharmacologic and pharmacokinetic distinctions that inform clinical recommendations. Currently, four agents, namely olaparib, rucaparib, niraparib, and talazoparib, have obtained approval in the United States and Europe. Olaparib, the first approved PARP inhibitor, has been extensively studied and is indicated for a wider range of cancer types.

Niraparib and talazoparib, the more recent additions to the PARP inhibitor class, possess the longest half-lives and are formulated for convenient once-daily dosing, alleviating the pill burden for patients when compared to older agents. Moreover, talazoparib undergoes minimal hepatic metabolism, reducing the potential for drug-drug interactions. Notably, niraparib is the sole PARP inhibitor recommended for dose reduction in hepatically impaired populations, whereas talazoparib and olaparib should be dose reduced in renally impaired populations. The mechanisms underlying these dose adjustment recommendations are further explored in this review.

Additionally, this review briefly covers veliparib, a PARP inhibitor under development, and two recently approved PARP inhibitors in China, fuzuloparib and pamiparib. Although significant progress has been made in understanding PARP inhibitors, there are several unanswered questions that remain, necessitating further research across a broader spectrum of cancer types within this evolving class of anticancer agents.

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PARP抑制剂:药理学、药代动力学和药物遗传学综述。
PARP抑制剂已成为一类有前景的抗癌药物,被批准用于治疗卵巢癌、乳腺癌、前列腺癌和胰腺癌癌症。这些抑制剂靶向参与DNA修复途径的PARP酶,并在负责修复DNA双链断裂的同源重组途径中存在遗传缺陷的癌症中表现出显著疗效。虽然所有PARP抑制剂都对参与DNA修复的关键酶PARP1和PARP2表现出有效和选择性的抑制作用,但该类药物中的每一种都具有独特的药理学特征,将它们彼此区分开来。本综述旨在全面检查整个PARP抑制剂类别的特性,同时强调个体药理学和药代动力学差异,为临床建议提供依据。目前,olaparib、rucaparib、niraparib和talazoparib四种制剂已在美国和欧洲获得批准。奥拉帕尼是首个获得批准的PARP抑制剂,已被广泛研究,适用于更广泛的癌症类型。Niraparib和talazoparib是PARP抑制剂类别中最新添加的药物,具有最长的半衰期,配方方便,每天给药一次,与较老的药物相比,减轻了患者的药物负担。此外,他拉唑帕尼的肝脏代谢最小,降低了药物相互作用的可能性。值得注意的是,尼拉帕利是唯一推荐用于减少肝功能受损人群剂量的PARP抑制剂,而塔拉佐帕尼和奥拉帕尼应在肾功能受损人群中减少剂量。本综述将进一步探讨这些剂量调整建议的机制。此外,本综述还简要介绍了正在开发的PARP抑制剂veliparib,以及中国最近批准的两种PARP抑制剂,呋唑帕利和帕帕帕利。尽管在理解PARP抑制剂方面取得了重大进展,但仍有几个悬而未决的问题,需要在这类不断发展的抗癌药物中对更广泛的癌症类型进行进一步研究。
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
Seminars in oncology
Seminars in oncology 医学-肿瘤学
CiteScore
6.60
自引率
0.00%
发文量
58
审稿时长
104 days
期刊介绍: Seminars in Oncology brings you current, authoritative, and practical reviews of developments in the etiology, diagnosis and management of cancer. Each issue examines topics of clinical importance, with an emphasis on providing both the basic knowledge needed to better understand a topic as well as evidence-based opinions from leaders in the field. Seminars in Oncology also seeks to be a venue for sharing a diversity of opinions including those that might be considered "outside the box". We welcome a healthy and respectful exchange of opinions and urge you to approach us with your insights as well as suggestions of topics that you deem worthy of coverage. By helping the reader understand the basic biology and the therapy of cancer as they learn the nuances from experts, all in a journal that encourages the exchange of ideas we aim to help move the treatment of cancer forward.
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