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.

中文翻译：

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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


药物开发是一个漫长的过程，可以促进和保护未来患者的健康和安全。非临床安全性研究遵循基本相似的设计，满足监管要求，但根据作用机制、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、临床病理和宏观病理通常提供足够的信息，以便通过大多数给药途径为关键研究选择剂量。吸入候选药物被认为在微观水平上对呼吸系统产生不利影响，否则这些影响可能是不可预测的;因此，与其他给药途径不同，吸入 DRF 研究通常包括呼吸道的组织病理学。组织病理学评估可能会使研究性新药 （IND） 申请时间表增加数周时间以及额外费用，但已被认为对于支持准确剂量选择以获得足够的安全边际是必要的，从而通过确保在关键研究中实现 NOAEL 来避免额外的研究和动物使用。因此，对 2018 年至 2021 年在 Labcorp 启动的 DRF 吸入研究进行了综述，以确定在初步吸入研究中纳入组织病理学是否有必要进行后续剂量选择。DRF 中的组织病理学发现影响了大约 45% 的大鼠和狗研究的关键吸入研究中的剂量选择。本综述确定了大鼠和狗的组织病理学发现，这些发现支持在 DRF 研究中继续纳入呼吸道组织病理学。 未来的调查将评估这些发现的潜在替代终点，这可能会将非临床药物开发时间缩短数周。