Point of departure (PoD) selection for the derivation of acceptable daily exposures (ADEs) for active pharmaceutical ingredients (APIs)
Point of departure (PoD) selection for the derivation of acceptable daily exposures (ADEs) for active pharmaceutical ingredients (APIs)
复制标题
DOI：
10.1016/j.yrtph.2016.05.028
复制
发表时间：
2016-08-15
影响因子：
3.4
通讯作者：
Weideman, Patricia A.
中科院分区：
文献类型：
--
作者：
Bercu, Joel P.;Morinello, Eric J.;Weideman, Patricia A.
药品生产的每日可接受暴露量（ADE）是一个基于健康的限值，用于确保在多产品设施中生产的药品是安全的，并用于验证质量过程。ADE推导的核心是选择适当的出发点（PoD），即，用于计算ADE的给定数据集的起始剂量。选择PoD涉及（1）数据收集和危害表征，（2）识别“关键效应”，以及（3）剂量反应评估，包括确定无明显不良作用水平（NOAEL）或最低明显不良作用水平（LOAEL），或计算基准剂量（BMD）水平。与其他类别的化学品相比，活性药物成分（API）具有良好的特征，并且具有独特的，丰富的数据集，在选择PoD时必须考虑这些数据集。API的数据集考虑因素包括治疗/药理作用、不同适应症和给药途径的API特性、药物开发期间的数据缺口和敏感亚群。因此，PoD分析必须由合格的毒理学家或其他了解药物数据集复杂性的专家进行。此外，随着制药行业不断发展新的治疗原则，PoD选择背后的科学也必须发展，以确保科学实践和由此产生的ADE。(C)2016 Elsevier Inc. All rights reserved.
The Acceptable Daily Exposure (ADE) derived for pharmaceutical manufacturing is a health-based limit used to ensure that medicines produced in multi-product facilities are safe and are used to validate quality processes. Core to ADE derivation is selecting appropriate point(s) of departure (PoD), i.e., the starting dose of a given dataset that is used in the calculation of the ADE. Selecting the PoD involves (1) data collection and hazard characterization, (2) identification of "critical effects", and (3) a dose-response assessment including the determination of the no-observed-adverse-effect-level (NOAEL) or lowest-observed-adverse-effect-level (LOAEL), or calculating a benchmark dose (BMD) level. Compared to other classes of chemicals, active pharmaceutical ingredients (APIs) are well-characterized and have unique, rich datasets that must be considered when selecting the PoD. Dataset considerations for an API include therapeutic/pharmacological effects, particularities of APIs for different indications and routes of administration, data gaps during drug development, and sensitive subpopulations. Thus, the PoD analysis must be performed by a qualified toxicologist or other expert who also understands the complexities of pharmaceutical datasets. In addition, as the pharmaceutical industry continues to evolve new therapeutic principles, the science behind PoD selection must also evolve to ensure state-of-the-science practices and resulting ADEs. (C) 2016 Elsevier Inc. All rights reserved.