Assessment of QT liabilities in drug development
Assessment of QT liabilities in drug development
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DOI：
10.1007/s10565-006-0141-x
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发表时间：
2007-01-01
影响因子：
6.1
通讯作者：
Crivori, P.
中科院分区：
文献类型：
--
作者：
Arrigoni, C.;Crivori, P.
自1997年CPMP（专利药品委员会）关于“评估非心血管药物延长QT间期的潜力”的文件发表以来，监管机构和制药行业都越来越重视对该主题进行仔细的临床前研究。监管部门的注意力集中在通过ICH（国际协调会议）程序起草安全药理学指南上，该过程导致ICH批准和ICH S7A指南被三个主要地区（美国、欧洲和日本）接受。该指南不仅涉及心血管研究，也不提供QT调查的指导。这部分已推迟到第二个指南（ICH S7B）。然而，制药公司已经实施了筛选策略，旨在选择不呈现QT负性的化合物。这些策略可以根据药物类别而有所不同，而实验模型根据化合物的发展阶段而有所不同。几种体外模型被用于发现（放射性配基结合、高通量膜片钳、外排和荧光测定）。这些模型与计算机方法相结合，使公司能够筛选大量化合物。其他在研发过程中应用的体外模型（动作电位持续时间，APD，在浦肯野纤维或乳头肌和离体心脏中）有助于更好地描述化合物在心脏离子通道上的活性。在有意识的非啮齿类动物中进行遥测研究是最可靠和公认的体内试验。
Since the publication, in 1997, of the CPMP (Committee for Proprietary Medicinal Products) Points to Consider document on "The assessment of potential for QT prolongation by non-cardiovascular medicinal products," both regulatory bodies and the pharmaceutical industry have paid increasing attention to the conduct of careful preclinical studies on the subject. Regulatory attention has focused on the drafting of Safety Pharmacology guidelines through the ICH (International Conference on Harmonization) process, which resulted in approval by the ICH and acceptance by the three main regions (USA, Europe, and Japan) of the ICH S7A guideline. The guideline does not deal only with cardiovascular studies and does not provide guidance on QT investigations. This part has been deferred to a second guideline (ICH S7B). Nevertheless, pharmaceutical companies have implemented screening strategies aimed at selecting compounds that do not present QT liabilities. These strategies can differ according to the pharmaceutical class, while experimental models differ according to the stage of development of the compound. Several in vitro models are employed in discovery (radioligand binding, high-throughput patch clamp, efflux, and fluorescence assays). These models, coupled with in silico methods, allow companies to screen a high number of compounds. Other in vitro models, applied later in the R&D process (action potential duration, APD, in Purkinje fibers or papillary muscle and the isolated heart) are useful in better describing the activity of compounds on cardiac ion channels. The most robust and accepted in vivo test is represented by telemetry studies in conscious non-rodents.