Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia Assay (CiPA): An industry survey on current practice

Authier, Simon; Pugsley, Michael K.; Koerner, John; Fermini, Bernard; Redfern, William S.; Valentin, Jean‐Pierre; Vargas, Hugo M.; Leishman, Derek J.; Correll, Krystle; Curtis, Michael J.

doi:10.1016/j.vascn.2017.02.021

Cited by 32 publications

(18 citation statements)

References 57 publications

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“…Our experiences with hSC-CM indicate that pro-arrhythmia risk assessment in hSC-CM is not ready for primetime. Our findings are consistent with the outcome of a recent industry survey conducted by the Safety Pharmacology Society (Authier et al, 2017 ), which reported that only 21% of responders considered hSC-CM representative of adult cardiomyocytes and provide reliable data as a nonclinical safety assay.…”

Section: Introductionsupporting

confidence: 92%

Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae

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Abi‐Gerges

et al. 2018

Front. Physiol.

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To assess drug-induced pro-arrhythmic risk, especially Torsades de Pointe (TdP), new models have been proposed, such as in-silico modeling of ventricular action potential (AP) and stem cell-derived cardiomyocytes (SC-CMs). Previously we evaluated the electrophysiological profile of 15 reference drugs in hESC-CMs and hiPSC-CMs for their effects on intracellular AP and extracellular field potential, respectively. Our findings indicated that SC-CMs exhibited immature phenotype and had the propensity to generate false positives in predicting TdP risk. To expand our knowledge with mature human cardiac tissues for drug-induced pro-arrhythmic risk assessment, human ventricular trabeculae (hVT) from ethically consented organ donors were used to evaluate the effects of the same 15 drugs (8 torsadogenic, 5 non-torsadogenic, and 2 discovery molecules) on AP parameters at 1 and 2 Hz. Each drug was tested blindly with 4 concentrations in duplicate trabeculae from 2 hearts. To identify the pro-arrhythmic risk of each drug, a pro-arrhythmic score was calculated as the weighted sum of percent drug-induced changes compared to baseline in various AP parameters, including AP duration and recognized pro-arrhythmia predictors such as triangulation, beat-to-beat variability and incidence of early-afterdepolarizations, at each concentration. In addition, to understand the translation of this preclinical hVT AP-based model to clinical studies, a ratio that relates each testing concentration to the human therapeutic unbound Cmax (Cmax) was calculated. At a ratio of 10, for the 8 torsadogenic drugs, 7 were correctly identified by the pro-arrhythmic score; 1 was mislabeled. For the 5 non-torsadogenic drugs, 4 were correctly identified as safe; 1 was mislabeled. Calculation of sensitivity, specificity, positive predictive value, and negative predictive value indicated excellent performance. For example, at a ratio of 10, scores for sensitivity, specificity, positive predictive value and negative predictive values were 0.88, 0.8, 0.88 and 0.8, respectively. Thus, the hVT AP-based model combined with the integrated analysis of pro-arrhythmic score can differentiate between torsadogenic and non-torsadogenic drugs, and has a greater predictive performance when compared to human SC-CM models.

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Section: Introductionsupporting

confidence: 92%

Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae

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Abi‐Gerges

et al. 2018

Front. Physiol.

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“…Consistent with the SPS tradition of publishing industry surveys on SP-related topics to inform on trends and practices in the field, [13][14][15][16][17] this survey explored important additional facets of CV SP. The present survey aimed to further examine current practices and strategies that are used principally by those drug safety scientists working in the pharmaceutical industry relative to CV SP model selection, study design, and data interpretation.…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, in a previous SPS survey, 17 the potential limitations to the use of hiPSC-CM in drug safety evaluations appeared numerous and included aspects such as reliability of the cells to represent adult cardiomyocyte phenotypes, stability of cardiac ion channel expression, and the financial impact to establish the assay. [17][18][19][20] However, responses in the current survey suggest that the implementation and use of hiPSC-CM has become less formidable, with 23% of responders now reporting frequent use of this in vitro assay. While this is likely attributed to both technological advances achieved with advanced engineering of hiPSC-CM as well as a plethora of published data using a multitude of drugs in recent years, there remains some concerns relative to the adult phenotype of the cells used in these emerging in vitro models.…”

Section: Discussionmentioning

confidence: 99%

An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation

Authier¹,

Abernathy

Correll

et al. 2020

Int J Toxicol

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Introduction: The Safety Pharmacology Society (SPS) conducted a membership survey to examine industry practices related mainly to cardiovascular (CV) safety pharmacology (SP). Methods: Questions addressed nonclinical study design, data analysis methods, drug-induced effects, and conventional and novel CV assays. Results: The most frequent therapeutic area targeted by drugs developed by the companies/institutions that employ survey responders was oncology. The most frequently observed drug-mediated effects included an increased heart rate, increased arterial blood pressure, hERG (IKr) block, decreased arterial blood pressure, decreased heart rate, QTc prolongation, and changes in body temperature. Broadly implemented study practices included Latin square crossover study design with n = 4 for nonrodent CV studies, statistical analysis of data (eg, analysis of variance), use of arrhythmia detection software, and the inclusion of data from all study animals when integrating SP studies into toxicology studies. Most responders frequently used individual animal housing conditions. Responders commonly evaluated drug effects on multiple ion channels, but in silico modeling methods were used much less frequently. Most responders rarely measured the J-Tpeak interval in CV studies. Uncertainties relative to Standard for Exchange of Nonclinical Data applications for data derived from CV SP studies were common. Although available, the use of human induced pluripotent stem cell cardiomyocytes remains rare. The respiratory SP study was rarely involved with identifying drug-induced functional issues. Responders indicated that the study-derived no observed effect level was more frequently determined than the no observed adverse effect level in CV SP studies; however, a large proportion of survey responders used neither.

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“…Additional references are provided. [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82]…”

Section: The Comprehensive In Vitro Proarrhythmia Assaymentioning

confidence: 99%

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

Turner

Rodríguez

Mantovani

et al. 2018

The Journal of Clinical Pharma

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Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety-related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability. ICH Guidelines S7B and E14 were released in 2005. Since then, they have been adopted by many regional regulatory authorities and have guided nonclinical and clinical proarrhythmic cardiac safety assessments during drug development. While this regulatory paradigm has been successful in preventing drugs with unanticipated potential for inducing the rare but potentially fatal polymorphic ventricular arrhythmia torsade de pointes from entering the market, it has led to the termination of drug development programs for other potentially useful medicines because of isolated results from studies with limited predictive value. Research efforts are now exploring alternative approaches to better predict potential proarrhythmic liabilities. For example, in the domain of human electrocardiographic assessments, concentration-response modeling conducted during phase 1 clinical development has recently become an accepted alternate primary methodology to the ICH E14 "thorough QT/QTc" study for defining a drug's corrected QT interval prolongation liability under certain conditions. When a drug's therapeutic benefit is considered important at a public health level but there is also an identified proarrhythmic liability that may result from administration of the single drug in certain individuals and/or drug-drug interactions, marketing approval will be accompanied by appropriate directions in the drug's prescribing information. Health-care professionals in the fields of medicine and pharmacy need to consider the prescribing information in conjunction with individual patients' clinical characteristics and concomitant medications when prescribing and dispensing such drugs.

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Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia Assay (CiPA): An industry survey on current practice

Abstract: Proarrhythmia liability assessment in drug development presently includes study types consistent with CiPA. It is anticipated that CiPA will develop into a workable solution to the concern that proarrhythmia liability testing remains suboptimal.

Cited by 32 publications

References 57 publications

Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae

Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae

An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

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