Sladen Louise, Matheson Rommel, Norton Kevin, Milne Aileen
Safety and ADME Translational Sciences Department, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Unit 310, Cambridge Science Park, Milton Road, Cambridge CB4 0FZ, UK.
Charles River, Safety Pharmacology, 22022 Transcanadienne, Senneville, QC H9X 3R3, Canada.
J Pharmacol Toxicol Methods. 2018 Sep-Oct;93:69-74. doi: 10.1016/j.vascn.2018.03.005. Epub 2018 Mar 23.
Assessment of effects of potential drug candidates on the respiratory system is part of the regulatory preclinical safety assessment conducted prior to first in human trials (FTIH). Commonly, this is carried out utilizing head out plethysmography (HOP) or whole body plethysmography (WBP) which record only ventilatory parameters. When dosing via the inhaled route a more thorough respiratory assessment, including a direct measure of airway mechanics, is desirable. The aim of the present work was to improve the strategy for respiratory safety testing by a) evaluating a telemetered pleural pressure - HOP (PP-HOP) model and b) evaluating a crossover study design protocol in the WBP model to reduce variability and animal usage.
For the PP- HOP model, rats were surgically implanted with a telemetry device for measurement of pleural pressure. Animals were placed in HOP tubes and respiratory function assessed when exposed to methacholine at doses of 0 (saline only), 0.42, 1.6 and 3.8 mg/kg. WBP assessment was performed in rats in a crossover study design when treated with theophylline at doses of 0 (saline only), 3, 10 and 30 mg/kg.
Data from the PP-HOP study confirmed the expected changes in ventilatory parameters and airway mechanics in response to inhaled methacholine, including an increase in pulmonary resistance and decrease in tidal volume. Data from the WBP crossover study demonstrated similar sensitivity and statistical power to detect changes in respiratory rate and tidal volume to a standard parallel group design.
Measurement of PP-HOP in a stand-alone safety pharmacology study in conjunction with HOP assessment conducted as part of a toxicology study, represents an improved respiratory testing strategy for inhaled drugs. For compounds administered by other routes, we conclude that use of WBP using a crossover dosing design is a suitable alternative to parallel dosing groups, with a significant reduction in animal numbers and no loss of statistical power.
评估潜在候选药物对呼吸系统的影响是在首次人体试验（FTIH）之前进行的监管临床前安全性评估的一部分。通常，这是利用头部露出式体积描记法（HOP）或全身体积描记法（WBP）来进行的，这些方法仅记录通气参数。当通过吸入途径给药时，需要进行更全面的呼吸评估，包括直接测量气道力学。本研究的目的是通过以下方式改进呼吸安全性测试策略：a）评估遥测胸膜压力-HOP（PP-HOP）模型，b）评估WBP模型中的交叉研究设计方案，以减少变异性和动物使用量。
对于PP-HOP模型，通过手术给大鼠植入用于测量胸膜压力的遥测装置。将动物置于HOP管中，当暴露于剂量为0（仅生理盐水）、0.42、1.6和3.8mg/kg的乙酰甲胆碱时评估呼吸功能。在交叉研究设计中，对用剂量为0（仅生理盐水）、3、10和30mg/kg的茶碱治疗的大鼠进行WBP评估。
PP-HOP研究的数据证实了吸入乙酰甲胆碱后通气参数和气道力学的预期变化，包括肺阻力增加和潮气量减少。WBP交叉研究的数据表明，与标准平行组设计相比，检测呼吸频率和潮气量变化具有相似的敏感性和统计功效。
在单独的安全药理学研究中测量PP-HOP，并结合作为毒理学研究一部分进行的HOP评估，代表了一种改进的吸入药物呼吸测试策略。对于通过其他途径给药的化合物，我们得出结论，采用交叉给药设计的WBP是平行给药组的合适替代方法，可显著减少动物数量且不损失统计功效。
