Early Drug Discovery Prediction of Proarrhythmia Potential and Its Covariates

Polak, Sebastian; Stockbridge, Norman; Garnett, Christine; Wiśniowska, Barbara

doi:10.1208/s12248-015-9773-1

Cited by 21 publications

(26 citation statements)

References 68 publications

(70 reference statements)

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“…Most critically, QT prolongation has been found to be an imperfect marker for drug-related pro-arrhythmic effects (torsade-de-pointes (TdP) arrhythmia) (Anon., 2005b; Shah, 2005). In addition, the current QT-focused strategy can result in the termination of safe and effective drugs, given the documented potential for false positives (Polak, Pugsley, Stockbridge, Garnett, & Wiśniowska, 2015; Stockbridge, Morganroth, Shah, & Garnett, 2013). As a result, the FDA has initiated the evaluation of alternative strategies and new preclinical models to provide a more reliable and cost effective pro-arrhythmic safety assessment.…”

Section: Introductionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

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While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

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Section: Introductionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

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“…Diabetes is strongly associated with cardiovascular diseases and symptoms including atrial fibrillation, atrial flutter, coronary artery disease and left ventricular hypertrophy [34] and can contribute to the development of diabetic cardiomyopathy [35]. Thus, the pathophysiological changes accompanying obesity and diabetes exert their effects both at the cellular and systemic levels resulting in cardiac dysfunction [23,36] Hence, the strategy of only examining the blockage of a single ion channel is increasingly being recognized as an imperfect measure ventricular repolarization [48,49].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, nonclinical QT prolongation assays are not fully predictive of the QT prolongation in humans [48].…”

Section: Introductionmentioning

confidence: 99%

“…Hence, although these guidelines have proven useful in decreasing drug-induced cardiotoxicity by enabling the early detection of potentially torsadogenic drugs, incidences of false positive results have led to the incorrect/inappropriate assignment of some drugs as torsadogenic [48]. In the case of some drugs, these approaches have also resulted in false negative results, leading to drug attrition [50][51][52].…”

Section: Introductionmentioning

confidence: 99%

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A role for in vitro disease models in the landscape of preclinical cardiotoxicity and safety testing

Varma

2017

JESR

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:Drug-induced cardiotoxicity is one of the predominant reasons for drug attrition and withdrawals. This is of critical concern when potentially cardiotoxic drugs are administered to individuals with inherited arrhythmogenic cardiac diseases or with metabolic diseases such as obesity and diabetes, which are key risk factors for cardiovascular diseases. Pathophysiological alteration prevalent under such conditions can alter or exacerbate cardiotoxic responses. The growing incidence of obesity, diabetes and metabolic syndrome subject a significant percentage of the population to drug treatments, thereby augmenting their risk for drug-induced cardiovascular toxicity. Hence, screening for drug-induced cardiotoxicity early in the preclinical stages of drug development, by using appropriate human disease models, can be effective in ensuring safety in clinical trials and preventing late stage and post-marketing drug withdrawals owing to cardiotoxicity. The advent of human pluripotent stem cells (hPSC) and induced pluripotent stem cell (iPSC)-derived cardiomyocytes are revolutionizing safety/toxicity screening in human cells by providing relevant human-specific, renewable model systems to explore human drug toxicity. The ability to generate patient-specific iPSCs that can model cardiac diseases, now offers a valuable option that can further improve drug safety assessments and enable a more accurate prediction of toxicity that occurs in the representative population that are prescribed the drugs. Use of appropriate disease models will not only provide cost savings by decreasing potential drug attrition and withdrawals, seen with many drugs, but will also be a promising option to advance precision medicine

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“…Most critically, QT prolongation has been found to be an imperfect marker for drug-related proarrhythmic effects (torsade-de-pointes (TdP) arrhythmia) (Anon., 2005b;Shah, 2005). In addition, the current QT-focused strategy can result in the termination of safe and effective drugs, given the documented potential for false positives (Polak, Pugsley, Stockbridge, Garnett, & Wiśniowska, 2015;Stockbridge, Morganroth, Shah, & Garnett, 2013). As a result, the FDA has initiated the evaluation of alternative strategies and new preclinical models to provide a more reliable and cost effective pro-arrhythmic safety assessment.…”

Section: Introductionmentioning

confidence: 99%

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Page

Ratchada

Miron

et al. 2016

Journal of Pharmacological and Toxicological Methods

View full text Add to dashboard Cite

While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced proarrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

show abstract

Early Drug Discovery Prediction of Proarrhythmia Potential and Its Covariates

Cited by 21 publications

References 68 publications

Human ex-vivo action potential model for pro-arrhythmia risk assessment

Human ex-vivo action potential model for pro-arrhythmia risk assessment

A role for in vitro disease models in the landscape of preclinical cardiotoxicity and safety testing

Human ex-vivo action potential model for pro-arrhythmia risk assessment

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