Wallis Rob, Benson Charles, Darpo Borje, Gintant Gary, Kanda Yasunari, Prasad Krishna, Strauss David G, Valentin Jean-Pierre
Royal Tunbridge Wells, TN3 9EA, UK.
Clinical Phamacology, Eli Lilly and Company, United States.
J Pharmacol Toxicol Methods. 2018 Sep-Oct;93:15-25. doi: 10.1016/j.vascn.2018.06.005. Epub 2018 Jun 27.
The Safety Pharmacology Society organized a scientific session at its annual conference in 2017 to discuss the challenges and opportunities of the Comprehensive In-Vitro Proarrhythmia Assay (CiPA) paradigm. Our intention was to raise awareness of this initiative with its members and also to gauge the extent to which safety pharmacologists have incorporated the CiPA testing strategy within the pharmaceutical industry. CiPA offers many potential opportunities including 1) a focus on proarrhythmic risk (as opposed to QTc prolongation), 2) providing scientific rationale to support the continued development of compounds that may have a poor selectivity over hERG whilst also blocking other inward currents and 3) reducing the extent of ECG monitoring in clinical trials with a greater influence of the non-clinical studies. Such opportunities may speed drug development and reduce costs. However, there are also challenges for CiPA implementation. For example, the mixed ion channel paradigm does not easily lend itself to a prospective drug discovery strategy although testing for such effects can be achieved with assays with good throughput. However, it should also be recognized that compounds with a mixed ion channel profile might also have properties that are undesirable to treat non-life threatening indications. All components of CiPA (nonclinical and clinical) require validation, particularly as a composite package to impact drug development and evaluation. One of the significant discussion points was that the existing regulatory guidance supports the use of components of CiPA through follow-up studies. A survey of the conference audience showed that the level of awareness of CiPA is quite high and that companies are already conducting some testing against a wider panel of cardiac ion channels beyond hERG. However, the adoption of other technologies (stem cell derived cardiac myocytes and in silico modeling) is less well developed. Taken together, the session demonstrated the potential advantages of CiPA, but also some significant challenges.
安全药理学协会在其2017年年度会议上组织了一场科学研讨会，以讨论全面体外致心律失常试验（CiPA）模式所面临的挑战和机遇。我们的目的是提高其成员对这一倡议的认识，并评估安全药理学家在制药行业内采用CiPA测试策略的程度。CiPA提供了许多潜在机会，包括1）关注致心律失常风险（与QTc延长相对），2）为支持对hERG选择性较差但同时阻断其他内向电流的化合物的持续研发提供科学依据，以及3）在临床试验中减少心电图监测的程度，同时增强非临床研究的影响力。这些机会可能会加快药物研发并降低成本。然而，CiPA的实施也存在挑战。例如，混合离子通道模式不容易适用于前瞻性药物发现策略，尽管可以通过高通量检测来实现此类效应的测试。然而，还应认识到，具有混合离子通道特征的化合物可能也具有治疗非危及生命适应症时不理想的特性。CiPA的所有组成部分（非临床和临床）都需要验证，尤其是作为影响药物研发和评估的综合方案。一个重要的讨论点是，现有监管指南通过后续研究支持CiPA各组成部分的使用。对会议听众的一项调查显示，对CiPA的认识水平相当高，并且各公司已经针对除hERG之外更广泛的心脏离子通道进行了一些测试。然而，其他技术（干细胞衍生心肌细胞和计算机模拟）的采用情况则不太成熟。总体而言，该研讨会展示了CiPA的潜在优势，但也存在一些重大挑战。
