Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart
Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart
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DOI：
10.1016/j.pbiomolbio.2005.06.006
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发表时间：
2006-01-01
影响因子：
3.8
通讯作者：
Lett, GS
中科院分区：
文献类型：
--
作者：
Bottino, D;Penland, RC;Lett, GS
延迟整流钾通道电流I-Kr的阻断与药物诱导的心电图QT间期延长和危及生命的心律失常相关。然而，越来越清楚的是，化合物诱导的与多个心脏离子通道的相互作用可能显著影响仅由I-Kr抑制引起的QT延长[Redfern，W.S.，卡尔森，L.，例如，2003.临床前心脏电生理学、临床QT间期延长与多种药物尖端扭转型室性心动过速之间的关系：药物开发中临时安全范围的证据。Cardiovasc. Res. 58（1），32-45]。由于多因素过程也具有时间依赖性和高度非线性，因此这种评估在体外可能不可行。有限的临床前数据、I-Kr hERG测定和犬浦肯野纤维（PF）动作电位（AP）[Gintant，G.A.，Limestine，J.T.，McDermott，J.S.，Wegner，C.D.，考克斯，B.F.，2001.犬浦肯野纤维：获得性长QT综合征和药物诱导的血管生成的体外模型系统。J. B.V. Pharmacol. 37（5），607-618]用于心脏电生理学的基于系统的建模平台中的两种测试化合物[Muzikant，A.L.，Penland，R.C.，2002.分析药物潜在QT间期延长风险的模型。Curr. Opin.药发现。Dev. 5（1），127-35]中描述的方法：（i）通过将功能电流参数训练成AP数据，将犬肌细胞模型转化为PF模型;（ii）逆向工程化合物对除I-Kr之外的五个通道电流的作用，预测I-Na+、I-持续和ICa 2+的显著IC 50值，随后通过实验验证;（111）使用预测的L型，（I-Na+、I-持续和I-Ca 2+、I-L-型）和测量的（I-Kr）IC 50值，以模拟化合物对内膜、中层心肌和心外膜心室细胞中AP的剂量依赖性作用;以及（iv）将三种类型的细胞反应整合到组织水平的空间模型中，其可定量地预测在以下剂量下，供试化合物不可能诱导QT延长或跨壁复极离散度增加-依赖和反向速率依赖的方式，尽管它们在体外抑制I-Kr。(c)2005年由Elsevier Ltd.出版
Blockade of the delayed rectifier potassium channel current, I-Kr, has been associated with drug-induced QT prolongation in the electrocardiogram and life-threatening cardiac arrhythmias. However, it is increasingly clear that compound-induced interactions with multiple cardiac ion channels may significantly affect QT prolongation that would result from inhibition of only I-Kr [Redfern, W.S., Carlsson, L., et al., 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58(1), 32-45]. Such an assessment may not be feasible in vitro, due to multifactorial processes that are also time-dependent and highly non-linear. Limited preclinical data, I-Kr hERG assay and canine Purkinje fiber (PF) action potentials (APs) [Gintant, G.A., Limberis, J.T., McDermott, J.S., Wegner, C.D., Cox, B.F., 2001. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J. Cardiovasc. Pharmacol. 37(5), 607-618], were used for two test compounds in a systems-based modeling platform of cardiac electrophysiology [Muzikant, A.L., Penland, R.C., 2002. Models for profiling the potential QT prolongation risk of drugs. Curr. Opin. Drug. Discov. Dev. 5(1), 127-35] to: (i) convert a canine myocyte model to a PF model by training functional current parameters to the AP data; (ii) reverse engineer the compounds' effects on five channel currents other than I-Kr, predicting significant IC50 values for I-Na+,I-sustained and ICa2+ which were subsequently experimentally validated; (111) use the predicted,L-type, (I-Na+,I-sustained and I-Ca2+,I-L-type) and measured (I-Kr) IC50 values to simulate dose-dependent effects of the compounds on APs in endocardial, mid-myocardial, and epicardiac ventricular cells; and (iv) integrate the three types of cellular responses into a tissue-level spatial model, which quantifiably predicted no potential for the test compounds to induce either QT prolongation or increased transmural dispersion of repolarization in a dose-dependent and reverse rate-dependent fashion, despite their inhibition of I-Kr in vitro. (c) 2005 Published by Elsevier Ltd.