Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, Connecticut.
Regulatory Strategy and Compliance, Pfizer Worldwide Research and Development, Groton, Connecticut.
Toxicol Sci. 2019 May 1;169(1):272-279. doi: 10.1093/toxsci/kfz035.
Cardiovascular (CV) safety-related attrition is an important contributor to the loss of promising drug candidates during development. CV safety pharmacology studies are conducted to identify these safety effects. Understanding translation of CV endpoints (specifically, heart rate [HR], and blood pressure [BP]) across preclinical animal models and to the clinic is critical in developing a robust CV derisking strategy. To this end, we investigated translation of HR and BP endpoints using data from 83 compounds that were tested in telemetry studies in rat and large animal (LA; dog or monkey) and 79 compounds that were tested in LA telemetry studies and human phase I clinical trials. Sensitivity, specificity as well as predictive values were calculated for rat to LA model comparison and for LA to human studies comparison. The rat CV model showed good concordance (sensitivity = 84% and specificity = 71%) for LA BP and HR changes. Similarly, LA CV measures of HR and BP showed good concordance (sensitivity = 78% and specificity = 79%) to clinical changes. The CV effects generally occurred within 0.3-3× free plasma concentration across species. Directionality of BP and HR change was conserved between LA to humans. However, for rat to LA comparisons the directionality of change was opposite for 23%-26% compounds. In conclusion, these data establish the translation of HR and BP from preclinical to clinical studies and emphasize the importance of preclinical animal models in the examination of CV safety of drugs.
心血管（CV）安全性相关淘汰是药物开发过程中丧失有前途候选药物的一个重要原因。进行 CV 安全药理学研究是为了识别这些安全性影响。了解 CV 终点（特别是心率[HR]和血压[BP]）在临床前动物模型和临床之间的转化对于制定稳健的 CV 风险降低策略至关重要。为此，我们使用来自 83 种在大鼠和大动物（犬或猴）遥测研究中进行测试的化合物以及在大动物遥测研究和人类 I 期临床试验中进行测试的 79 种化合物的数据，研究了 HR 和 BP 终点的转化。计算了大鼠与大动物模型比较以及大动物与人类研究比较的敏感性、特异性和预测值。大鼠 CV 模型对大动物 BP 和 HR 变化的一致性较好（敏感性=84%，特异性=71%）。同样，大动物 CV 测量的 HR 和 BP 与临床变化具有较好的一致性（敏感性=78%，特异性=79%）。CV 效应通常在跨物种的 0.3-3×游离血浆浓度范围内发生。BP 和 HR 变化的方向性在大动物到人类之间保持一致。然而，对于大鼠与大动物的比较，有 23%-26%的化合物的变化方向相反。总之，这些数据确立了 HR 和 BP 从临床前到临床研究的转化，并强调了临床前动物模型在药物 CV 安全性检查中的重要性。
