Evolution of Strategies to Improve Preclinical Cardiac Safety Testing

Overview

Journal Nat Rev Drug Discov

Specialty Pharmacology

Date 2016 Feb 20

PMID 26893184

Citations 142

Authors

Gary Gintant

Philip T Sager

Norman Stockbridge

Affiliations

Soon will be listed here.

Abstract

The early and efficient assessment of cardiac safety liabilities is essential to confidently advance novel drug candidates. This article discusses evolving mechanistically based preclinical strategies for detecting drug-induced electrophysiological and structural cardiotoxicity using in vitro human ion channel assays, human-based in silico reconstructions and human stem cell-derived cardiomyocytes. These strategies represent a paradigm shift from current approaches, which rely on simplistic in vitro assays that measure blockade of the Kv11.1 current (also known as the hERG current or IKr) and on the use of non-human cells or tissues. These new strategies have the potential to improve sensitivity and specificity in the early detection of genuine cardiotoxicity risks, thereby reducing the likelihood of mistakenly discarding viable drug candidates and speeding the progression of worthy drugs into clinical trials.

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References

Mirams G, Davies M, Brough S, Bridgland-Taylor M, Cui Y, Gavaghan D . Prediction of Thorough QT study results using action potential simulations based on ion channel screens. J Pharmacol Toxicol Methods. 2014; 70(3):246-54. PMC: 4266452. DOI: 10.1016/j.vascn.2014.07.002. View

Chang M, Chang C, de Lange E, Xu L, ORourke B, Karagueuzian H . Dynamics of early afterdepolarization-mediated triggered activity in cardiac monolayers. Biophys J. 2012; 102(12):2706-14. PMC: 3379011. DOI: 10.1016/j.bpj.2012.05.011. View

Di Veroli G, Davies M, Zhang H, Abi-Gerges N, Boyett M . hERG inhibitors with similar potency but different binding kinetics do not pose the same proarrhythmic risk: implications for drug safety assessment. J Cardiovasc Electrophysiol. 2013; 25(2):197-207. DOI: 10.1111/jce.12289. View

Woosley R, Chen Y, Freiman J, GILLIS R . Mechanism of the cardiotoxic actions of terfenadine. JAMA. 1993; 269(12):1532-6. View

Robertson C, Tran D, George S . Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells. 2013; 31(5):829-37. PMC: 3749929. DOI: 10.1002/stem.1331. View

Qu Y, Gao B, Fang M, Vargas H . Human embryonic stem cell derived cardiac myocytes detect hERG-mediated repolarization effects, but not Nav1.5 induced depolarization delay. J Pharmacol Toxicol Methods. 2013; 68(1):74-81. DOI: 10.1016/j.vascn.2013.03.001. View

Zhang S, Zhou Z, Gong Q, Makielski J, January C . Mechanism of block and identification of the verapamil binding domain to HERG potassium channels. Circ Res. 1999; 84(9):989-98. DOI: 10.1161/01.res.84.9.989. View

Rao C, Prodromakis T, Kolker L, Chaudhry U, Trantidou T, Sridhar A . The effect of microgrooved culture substrates on calcium cycling of cardiac myocytes derived from human induced pluripotent stem cells. Biomaterials. 2012; 34(10):2399-411. PMC: 3605579. DOI: 10.1016/j.biomaterials.2012.11.055. View

Li J, Cousin C, Tinkler H, Touhami J, Petit V, Thomas N . Profiling of Nutrient Transporter Expression in Human Stem Cell-Derived Cardiomyocytes Exposed to Tyrosine Kinase Inhibitor Anticancer Drugs Using RBD Ligands. J Biomol Screen. 2014; 19(8):1185-92. DOI: 10.1177/1087057114533724. View

10.

Bers D, Bassani J, Bassani R . Na-Ca exchange and Ca fluxes during contraction and relaxation in mammalian ventricular muscle. Ann N Y Acad Sci. 1996; 779:430-42. DOI: 10.1111/j.1749-6632.1996.tb44818.x. View

11.

Roden D . Early after-depolarizations and torsade de pointes: implications for the control of cardiac arrhythmias by prolonging repolarization. Eur Heart J. 1993; 14 Suppl H:56-61. DOI: 10.1093/eurheartj/14.suppl_h.56. View

12.

OBrien P, Irwin W, Diaz D, Howard-Cofield E, Krejsa C, Slaughter M . High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screening. Arch Toxicol. 2006; 80(9):580-604. DOI: 10.1007/s00204-006-0091-3. View

13.

Carlson C, Koonce C, Aoyama N, Einhorn S, Fiene S, Thompson A . Phenotypic screening with human iPS cell-derived cardiomyocytes: HTS-compatible assays for interrogating cardiac hypertrophy. J Biomol Screen. 2013; 18(10):1203-11. DOI: 10.1177/1087057113500812. View

14.

Grilo L, Carrupt P, Abriel H . Stereoselective Inhibition of the hERG1 Potassium Channel. Front Pharmacol. 2011; 1:137. PMC: 3153011. DOI: 10.3389/fphar.2010.00137. View

15.

Lacerda A, Kuryshev Y, Chen Y, Renganathan M, Eng H, Danthi S . Alfuzosin delays cardiac repolarization by a novel mechanism. J Pharmacol Exp Ther. 2007; 324(2):427-33. DOI: 10.1124/jpet.107.128405. View

16.

Christophe B . Simulation of early after-depolarisation in non-failing human ventricular myocytes: can this help cardiac safety pharmacology?. Pharmacol Rep. 2014; 65(5):1281-93. DOI: 10.1016/s1734-1140(13)71486-5. View

17.

Kaestner L, Lipp P . Screening action potentials: the power of light. Front Pharmacol. 2011; 2:42. PMC: 3147179. DOI: 10.3389/fphar.2011.00042. View

18.

OHara T, Rudy Y . Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species. Am J Physiol Heart Circ Physiol. 2011; 302(5):H1023-30. PMC: 3311457. DOI: 10.1152/ajpheart.00785.2011. View

19.

Clements M, Thomas N . High-throughput multi-parameter profiling of electrophysiological drug effects in human embryonic stem cell derived cardiomyocytes using multi-electrode arrays. Toxicol Sci. 2014; 140(2):445-61. DOI: 10.1093/toxsci/kfu084. View

20.

Lee J, Berg E . Neoclassic drug discovery: the case for lead generation using phenotypic and functional approaches. J Biomol Screen. 2013; 18(10):1143-55. DOI: 10.1177/1087057113506118. View