CiPA: Ongoing testing, future qualification procedures, and pending issues

Cavero, Icilio; Holzgrefe, Henry H.

doi:10.1016/j.vascn.2015.06.004

Cited by 36 publications

(28 citation statements)

References 44 publications

(51 reference statements)

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“…A comparable situation applies to the extrapolation of QT prolongation from controlled clinical trials to a real‐life setting (Chain et al , ). This should be carefully considered by those supporting the CiPA working groups, who are currently responsible for the development and implementation of alternative guidelines for ICH S7B, which will ultimately guide the ranking of compounds in terms of their pro‐arrhythmic risk (Cavero and Holzgrefe, ).…”

Section: Discussionmentioning

confidence: 99%

“…As a result, at the conference of the Cardiac Safety Research Consortium (CSRC)–Health and Environmental Sciences Institute (HESI)–Food and Drug Administration (FDA) held in July 2013, a revision of ICH S7B and possible elimination of ICH‐E14 were proposed. The proposal is aimed at shifting the focus from evaluating QT prolongation to evaluating the pro‐arrhythmic activity of a compound using a comprehensive in vitro pro‐arrhythmia assay (CiPA) (Cavero and Holzgrefe, ; Sager et al , ; Fermini et al , ). The approach seems, however, to overlook the importance of a stricter quantitative framework for the translation of in vitro findings and in particular of the potential differences between in vitro and in vivo concentration–effect [pharmacokinetic–pharmacodynamic (PKPD)] relationships.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic–pharmacodynamic modelling of drug‐induced QTc interval prolongation in man: prediction from in vitro human ether‐à‐go‐go‐related gene binding and functional inhibition assays and conscious dog studies

Dubois

Casarotto

Danhof

et al. 2016

British J Pharmacology

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The lack of standardized protocols for in vitro assays leads to significant differences in experimental conditions, making the assessment of in vitro-in vivo correlations unreliable. Identification of an accurate safety window during the screening of candidate molecules requires a quantitative framework that disentangles system- from drug-specific properties under physiological conditions, enabling translation of the results to humans. Similar considerations will be relevant for the comprehensive in vitro pro-arrhythmia assay initiative.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic modelling of drug‐induced QTc interval prolongation in man: prediction from in vitro human ether‐à‐go‐go‐related gene binding and functional inhibition assays and conscious dog studies

Dubois

Casarotto

Danhof

et al. 2016

British J Pharmacology

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“…94 Expert working groups are tasked with developing and testing detailed protocols for each of the 3 components, which will be validated by testing 29 established drugs spanning the range from low to high proarrhythmic liability. 95,96 Once established, CiPA may remove the need for expensive Thorough QT studies for most drug candidates.…”

Section: Integrated Cardiac Safety Assessmentmentioning

confidence: 99%

Cardiac ion channels

Priest

McDermott

2015

Channels

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Ion channels are critical for all aspects of cardiac function, including rhythmicity and contractility. Consequently, ion channels are key targets for therapeutics aimed at cardiac pathophysiologies such as atrial fibrillation or angina. At the same time, off-target interactions of drugs with cardiac ion channels can be the cause of unwanted side effects. This manuscript aims to review the physiology and pharmacology of key cardiac ion channels. The intent is to highlight recent developments for therapeutic development, as well as elucidate potential mechanisms for drug-induced cardiac side effects, rather than present an in-depth review of each channel subtype.

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“…The importance of investigating these side effects is emphasized by regulatory guidelines and documents currently in development. 2 High-throughput screening assays for ion channels have been established in pharmaceutical companies using indirect readout technologies, often with fluorescent assays, e.g., by monitoring the change of the cellular potential with potentiometric dyes, or by fluorescence-labeling known ligands. 3 These methods provide an indirect measure of ion channel function.…”

Section: Introductionmentioning

confidence: 99%

“…23,24 Recently the Food and Drug Administration (FDA) and the Health and Environmental Sciences Institute (HESI) started a new initiative to evaluate the potential for integrated non-clinical cardiac ion channel activity assessment to predict the clinical pro-arrhythmic risk of drugs. 2,25 Included in this is the evaluation of the use of pluripotent stem cell applications for cardiovascular risk assessment. So far, the Patchliner has been used successfully to record from mouse embryonic stem cells (CorAt, Axiogenesis), 10 human iPS cells from CDI, 14,26 Axiogenesis (Cor.4U) 26 ), and Cellectis ( Fig.…”

mentioning

confidence: 99%