Inclusion of Histopathology in Dose Range-Finding Nonclinical Studies for Inhaled Drug Products.

IF 1.2 4区 医学 Q4 PHARMACOLOGY & PHARMACY
International Journal of Toxicology Pub Date : 2024-12-01 Epub Date: 2024-08-29 DOI:10.1177/10915818241276439
Emily A Resseguie, Helen Palmer
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引用次数: 0

Abstract

Drug development is a lengthy process that promotes and protects the health and safety of future patients. Nonclinical safety studies follow essentially similar designs that fulfill regulatory requirements but are amended based on factors including the mechanism of action, class of molecule, and route of administration. Clinical observations, clinical pathology, and macroscopic pathology in dose range-finding (DRF) studies generally provide sufficient information to select doses for pivotal studies by most delivery routes. Inhaled drug candidates are recognized for producing adverse effects on the respiratory system at the microscopic level that may otherwise be unpredictable; therefore, unlike other routes of administration, inhalation DRF studies typically include histopathology of the respiratory tract. Histopathology evaluations can add several weeks to the Investigational New Drug (IND) application timeline along with additional costs but have been considered necessary to support accurate dose selection for adequate safety margins, thereby potentially avoiding additional studies and animal usage by ensuring achievement of a NOAEL in the pivotal studies. Therefore, DRF inhalation studies initiated from 2018 to 2021 at Labcorp were reviewed to determine whether inclusion of histopathology on preliminary inhalation studies was necessary for subsequent dose selection. Histopathology findings in the DRF impacted dose selection in pivotal inhalation studies for approximately 45% of rat and dog studies. This review identified histopathology findings in rat and dog that support continued inclusion of respiratory tract histopathology in DRF studies. Future investigations will evaluate potential surrogate endpoints for these findings, which could reduce nonclinical drug development timelines by several weeks.

将组织病理学纳入吸入药物产品的剂量范围探索非临床研究。
药物研发是一个漫长的过程,旨在促进和保护未来患者的健康和安全。非临床安全性研究基本上采用类似的设计,以满足监管要求,但会根据作用机制、分子类别和给药途径等因素进行修改。剂量范围探索(DRF)研究中的临床观察、临床病理学和宏观病理学通常为大多数给药途径的关键性研究提供了足够的剂量选择信息。吸入候选药物被认为会在微观层面上对呼吸系统产生不良影响,而这些影响可能是无法预测的;因此,与其他给药途径不同,吸入 DRF 研究通常包括呼吸道组织病理学检查。组织病理学评估会使新药研究(IND)申请时间延长数周,并增加额外成本,但被认为是支持准确剂量选择以获得足够安全系数的必要手段,从而通过确保在关键研究中达到无观测不良效应水平,避免额外的研究和动物使用。因此,对 Labcorp 于 2018 年至 2021 年启动的 DRF 吸入研究进行了审查,以确定是否有必要在初步吸入研究中纳入组织病理学,以便进行后续剂量选择。在约45%的大鼠和狗研究中,DRF中的组织病理学结果影响了关键吸入研究中的剂量选择。本次审查确定了大鼠和狗的组织病理学结果,支持继续将呼吸道组织病理学纳入 DRF 研究。未来的研究将评估这些发现的潜在替代终点,这可将非临床药物开发的时间缩短数周。
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来源期刊
CiteScore
3.40
自引率
4.50%
发文量
53
审稿时长
4.5 months
期刊介绍: The International Journal of Toxicology publishes timely, peer-reviewed papers on current topics important to toxicologists. Six bi-monthly issues cover a wide range of topics, including contemporary issues in toxicology, safety assessments, novel approaches to toxicological testing, mechanisms of toxicity, biomarkers, and risk assessment. The Journal also publishes invited reviews on contemporary topics, and features articles based on symposia. In addition, supplemental issues are routinely published on various special topics, including three supplements devoted to contributions from the Cosmetic Review Expert Panel.
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