Murphy Dennis J
Department of Safety Pharmacology, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA.
Regul Toxicol Pharmacol. 2016 Nov;81:194-200. doi: 10.1016/j.yrtph.2016.07.001. Epub 2016 Jul 21.
Current practice in respiratory safety pharmacology generally follows the regulatory guidance provided by the ICH document S7A and focuses on measures of pulmonary ventilation. What these measures do not account for is the ability of drugs to cause ventilatory instability or interruptions in ventilatory rhythm. Ventilatory instability can be identified by the presence of prolonged end-expiratory pauses or apneic periods. An apneic event has been defined as an apneic period of sufficient duration to cause hypoxia (i.e., decrease in hemoglobin oxygen saturation ≥ 3%). Repeated apneic events are often referred to as intermittent hypoxia. Characterizing ventilatory instability is important since (1) occurrence of apneic events in humans can lead to serious adverse outcomes such as systemic and pulmonary hypertension, cardiac arrhythmia, stroke, CNS dysfunction, metabolic disorders, enhanced tumor growth and death, (2) drugs are known to cause or exacerbate apneic events in humans, and (3) there is a preexisting condition of ventilatory instability referred to as sleep apnea that is prevalent in the human population. Evaluating this new target in respiratory safety pharmacology studies is needed to ensure that the potential for new drugs to cause or exacerbate apneic events can be identified and the impact on patient safety characterized.
目前呼吸安全药理学的实践通常遵循国际人用药品注册技术协调会（ICH）文件S7A提供的监管指南，并侧重于肺通气的测量。这些测量没有考虑到药物导致通气不稳定或通气节律中断的能力。通气不稳定可通过呼气末延长停顿或呼吸暂停期来识别。呼吸暂停事件被定义为持续时间足以导致缺氧的呼吸暂停期（即血红蛋白氧饱和度下降≥3%）。反复的呼吸暂停事件通常被称为间歇性缺氧。表征通气不稳定很重要，因为（1）人类呼吸暂停事件的发生可导致严重不良后果，如全身性和肺动脉高压、心律失常、中风、中枢神经系统功能障碍、代谢紊乱、肿瘤生长加速和死亡，（2）已知药物会导致或加剧人类的呼吸暂停事件，（3）存在一种称为睡眠呼吸暂停的通气不稳定的预先存在情况，在人群中很普遍。在呼吸安全药理学研究中评估这个新靶点是必要的，以确保能够识别新药导致或加剧呼吸暂停事件的可能性，并确定其对患者安全的影响。
