Comprehensive in vitro Proarrhythmia Assay (C i PA): Pending issues for successful validation and implementation

Cavero, Icilio; Guillon, Jean‐Michel; Ballet, Véronique; Clements, Mike; Gerbeau, Jean-Frédéric; Holzgrefe, Henry H.

doi:10.1016/j.vascn.2016.05.012

Cited by 34 publications

(22 citation statements)

References 70 publications

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“…Over the last few years, the comprehensive in vitro proarrythmia assay (CiPA) initiative has been advocating the in vitro assessment of multiple cardiac ion currents and the estimation of the combined effect of multiple ionic channel inhibition using cardiomyocyte cell-based quantitative systems models (17,18). However, the primary focus of the CiPA has been on the parent drug, specifically at the single cardiac cell level (19). Assessment of the QT prolongation liability of a drug based only on the parent drug and the hERG-centric evaluations could be misleading since many drugs such as CT affect not only I Kr but also other ionic currents and may have electrophysiologically active metabolites (14,20).…”

Section: Introductionmentioning

confidence: 99%

Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram

Patel

Wiśniowska

Jamei

et al. 2017

AAPS J

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Abstract.A quantitative systems toxicology (QST) model for citalopram was established to simulate, in silico, a 'virtual twin' of a real patient to predict the occurrence of cardiotoxic events previously reported in patients under various clinical conditions. The QST model considers the effects of citalopram and its most notable electrophysiologically active primary (desmethylcitalopram) and secondary (didesmethylcitalopram) metabolites, on cardiac electrophysiology. The in vitro cardiac ion channel current inhibition data was coupled with the biophysically detailed model of human cardiac electrophysiology to investigate the impact of (i) the inhibition of multiple ion currents (I Kr , I Ks , I CaL ); (ii) the inclusion of metabolites in the QST model; and (iii) unbound or total plasma as the operating drug concentration, in predicting clinically observed QT prolongation. The inclusion of multiple ion channel current inhibition and metabolites in the simulation with unbound plasma citalopram concentration provided the lowest prediction error. The predictive performance of the model was verified with three additional therapeutic and supra-therapeutic drug exposure clinical cases. The results indicate that considering only the hERG ion channel inhibition of only the parent drug is potentially misleading, and the inclusion of active metabolite data and the influence of other ion channel currents should be considered to improve the prediction of potential cardiac toxicity. Mechanistic modelling can help bridge the gaps existing in the quantitative translation from preclinical cardiac safety assessment to clinical toxicology. Moreover, this study shows that the QST models, in combination with appropriate drug and systems parameters, can pave the way towards personalised safety assessment.

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Section: Introductionmentioning

confidence: 99%

Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram

Patel

Wiśniowska

Jamei

et al. 2017

AAPS J

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“…72 Because it is unclear which aspects of network firing activity (i.e., action potential width, bursting, mean activity, interspike statistics, oscillations) are most important for cognitive function, traditional classifiers or deep-learning approaches could be used to predict what property of simulated activity is associated with human cognition. A similar approach has been followed in the Comprehensive in Vitro ProArrythmia Assay (CiPA) 73 or Consortium for Safety Assessment using hiPSCs, 74 with the objective to develop a predictive model for cardiac safety based on electrophysiological data with human iPSC differentiated into cardiomyocytes.…”

Section: Use Of Qsp In Phenotypical Drug Discoverymentioning

confidence: 99%

Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges

Geerts

Wikswo

Graaf³

et al. 2019

CPT Pharmacom & Syst Pharma

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The substantial progress made in the basic sciences of the brain has yet to be adequately translated to successful clinical therapeutics to treat central nervous system (CNS) diseases. Possible explanations include the lack of quantitative and validated biomarkers, the subjective nature of many clinical endpoints, and complex pharmacokinetic/pharmacodynamic relationships, but also the possibility that highly selective drugs in the CNS do not reflect the complex interactions of different brain circuits. Although computational systems pharmacology modeling designed to capture essential components of complex biological systems has been increasingly accepted in pharmaceutical research and development for oncology, inflammation, and metabolic disorders, the uptake in the CNS field has been very modest. In this article, a cross-disciplinary group with representatives from academia, pharma, regulatory, and funding agencies make the case that the identification and exploitation of CNS therapeutic targets for drug discovery and development can benefit greatly from a system and network approach that can span the gap between molecular pathways and the neuronal circuits that ultimately regulate brain activity and behavior.

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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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Comprehensive in vitro Proarrhythmia Assay (C i PA): Pending issues for successful validation and implementation

Cited by 34 publications

References 70 publications

Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram

Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram

Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges

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

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