The Concordance between Nonclinical and Phase I Clinical Cardiovascular Assessment from a Cross-Company Data Sharing Initiative

Ewart, Lorna; Aylott, Mike; Deurinck, Mark; Engwall, Michael; Gallacher, David J.; Geys, Helena; Jarvis, Philip; Ju, Haisong; Leishman, Derek J.; Leong, Louise; McMahon, Nick; Mead, Andy N.; Milliken, Phil; Suter, Willi; Teisman, Ard; Ammel, Karel Van; Vargas, Hugo M.; Wallis, Rob; Valentin, Jean‐Pierre

doi:10.1093/toxsci/kfu198

Cited by 66 publications

(64 citation statements)

References 30 publications

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“…Similar to results from Ewart et al . (), assay sensitivity in the present study was low at therapeutic exposures (0.14), with both results substantially lower than reported by Wallis (0.83; Wallis, ). As in the present study, the data set from Ewart et al .…”

Section: Discussioncontrasting

confidence: 85%

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Can non‐clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium

Park

Gintant

et al. 2018

British J Pharmacology

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Background and Purpose Translation of non‐clinical markers of delayed ventricular repolarization to clinical prolongation of the QT interval corrected for heart rate (QTc) (a biomarker for torsades de pointes proarrhythmia) remains an issue in drug discovery and regulatory evaluations. We retrospectively analysed 150 drug applications in a US Food and Drug Administration database to determine the utility of established non‐clinical in vitro IKr current human ether‐à‐go‐go‐related gene (hERG), action potential duration (APD) and in vivo (QTc) repolarization assays to detect and predict clinical QTc prolongation. Experimental Approach The predictive performance of three non‐clinical assays was compared with clinical thorough QT study outcomes based on free clinical plasma drug concentrations using sensitivity and specificity, receiver operating characteristic (ROC) curves, positive (PPVs) and negative predictive values (NPVs) and likelihood ratios (LRs). Key Results Non‐clinical assays demonstrated robust specificity (high true negative rate) but poor sensitivity (low true positive rate) for clinical QTc prolongation at low‐intermediate (1×–30×) clinical exposure multiples. The QTc assay provided the most robust PPVs and NPVs (ability to predict clinical QTc prolongation). ROC curves (overall test accuracy) and LRs (ability to influence post‐test probabilities) demonstrated overall marginal performance for hERG and QTc assays (best at 30× exposures), while the APD assay demonstrated minimal value. Conclusions and Implications The predictive value of hERG, APD and QTc assays varies, with drug concentrations strongly affecting translational performance. While useful in guiding preclinical candidates without clinical QT prolongation, hERG and QTc repolarization assays provide greater value compared with the APD assay.

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Section: Discussioncontrasting

confidence: 85%

“…The in vivo QTc assay had specificity values comparable with previous results from Wallis () and Ewart et al . () (1.0, 0.86 and 0.98, respectively) at clinically relevant exposures, consistent with a low false‐positive rate with this assay. Similar to results from Ewart et al .…”

Section: Discussionsupporting

confidence: 73%

Can non‐clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium

Park

Gintant

et al. 2018

British J Pharmacology

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“…The TQT study is designed to characterize the potential effects of a drug candidate on ventricular repolarization in order to determine if additional cardiac monitoring is required. While TQT studies have been relatively effective in preventing approval and marketing of new drugs with strong pro-arrhythmic potential (Ewart et al, 2014; Vargas et al, 2015), the strategy has significant shortcomings. 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).…”

Section: Introductionmentioning

confidence: 99%

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

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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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“…The TQT study is designed to characterize the potential effects of a drug candidate on ventricular repolarization in order to determine if additional cardiac monitoring is required. While TQT studies have been relatively effective in preventing approval and marketing of new drugs with strong pro-arrhythmic potential (Ewart et al, 2014;Vargas et al, 2015), the strategy has significant shortcomings. 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).…”

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

The Concordance between Nonclinical and Phase I Clinical Cardiovascular Assessment from a Cross-Company Data Sharing Initiative

Cited by 66 publications

References 30 publications

Can non‐clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium

Can non‐clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium

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

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

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