Evaluation of the Rabbit Purkinje Fibre Assay as an in vitro Tool for Assessing the Risk of Drug-Induced Torsades de Pointes in Humans

Aubert, Marion; Osterwalder, Rolf; Wagner, Björn; Parrilla, Isabelle; Cavero, Icilio; Doessegger, Lucette; Ertel, Eric A.

doi:10.2165/00002018-200629030-00007

Cited by 40 publications

(22 citation statements)

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“…Both the Food and Drug Administration and the European Medicines Agency recommend the Purkinje fiber assay for in vitro electrophysiological studies as valuable for assessing potential arrhythmogenicity of a tested compound (41). Aubert et al (2) have specifically evaluated the rabbit Purkinje fiber assay on 26 potentially arrhythmogenic compounds. They found that the number of false positives and false negatives was better than any similar assay from other animal species.…”

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confidence: 99%

Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers

Corrias

Giles

Rodríguez

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Corrias A, Giles W, Rodriguez B. Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers. Am J Physiol Heart Circ Physiol 300: H1806-H1813, 2011. First published February 18, 2011 doi:10.1152/ajpheart.01170.2010.-Purkinje cells play an important role in drug-induced arrhythmogenesis and are widely used in preclinical drug safety assessments. Repolarization abnormalities such as action potential (AP) prolongation and early afterdeploarizations (EAD) are often observed in vitro upon pharmacological interventions. However, because drugs do not act on only one defined target, it is often difficult to fully explain the mechanisms of action and their potential arrhythmogenicity. Computational models, when appropriately detailed and validated, can be used to gain mechanistic insights into the mechanisms of action of certain drugs. Nevertheless, no model of Purkinje electrophysiology that is able to reproduce characteristic Purkinje responses to drug-induced changes in ionic current conductances such as AP prolongation and EAD generation currently exists. In this study, a novel biophysically detailed model of rabbit Purkinje electrophysiology was developed by integration of data from voltage-clamp and AP experimental recordings. Upon validation, we demonstrate that the model reproduces many key electrophysiological properties of rabbit Purkinje cells. These include: AP morphology and duration, both input resistance and rate dependence properties as well as response to hyperkalemia. Pharmacological interventions such as inward rectifier K ϩ current and rapid delayed rectifier K ϩ current block as well as late Na ϩ current increase result in significant AP changes. However, enhanced L-type Ca 2ϩ current (iCaL) dominates in EAD genesis in Purkinje fibers. In addition, iCaL inactivation dynamics and intercellular coupling in tissue strongly modulate EAD formation. We conclude that EAD generation in Purkinje cells is mediated by an increase in iCaL and modulated by its inactivation kinetics. electrophysiology; Purkinje; early afterdepolarization; arrhythmia FOR DECADES, PURKINJE FIBERS have been implicated in the initiation of lethal cardiac arrhythmias such as ventricular fibrillation and Torsades de Pointes in a variety of clinical situations. In patients with congenital long QT syndrome or Brugada syndrome, for example, the Purkinje-myocardial interface is often the location where ventricular fibrillation initiated (15). Adverse side effects of drugs belonging to a broad range of categories are important factors that have long been associated with arrhythmogenesis. Regulatory agencies have identified Purkinje fibers as an important tool in preclinical assessment of drug safety. Both the Food and Drug Administration and the European Medicines Agency recommend the Purkinje fiber assay for in vitro electrophysiological studies as valuable for assessing potential arrhythmogenicity of a tested compound (41). Aubert et al. (2) have specifically evaluated the rabbit Purkinj...

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confidence: 99%

Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers

Corrias

Giles

Rodríguez

2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Thus, it appears that it is a highly specific and sensitive model to investigate drug-induced TdP liability. Over the years, the assay has been well validated through the testing of many reference compounds (see Champeroux et al 2005;Hanson et al 2006;Aubert et al 2006;Puddu et al 2011) for use in the early de-risking stages of development (as a non-GLP assay) or as a component of the GLP-compliant in vitro core battery testing scheme. Over the years, the assay has been well validated through the testing of many reference compounds (see Champeroux et al 2005;Hanson et al 2006;Aubert et al 2006;Puddu et al 2011) for use in the early de-risking stages of development (as a non-GLP assay) or as a component of the GLP-compliant in vitro core battery testing scheme.…”

Section: The Isolated Purkinje Fibrementioning

confidence: 99%

Principles of Safety Pharmacology

2015

Handbook of Experimental Pharmacology

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“…Variations on the AP shape are indicative of the potential effects of the substance on the main cardiac ionic currents such as the rapid sodium current (I Na ) responsible for the rapid cell depolarization (phase 0 of the AP) and involved in cell electrical conductance, the transient outward potassium current (I Kto ) responsible for the notch specific to the Purkinje fiber AP (phase 1 of the AP), the slow calcium current (I CaL ) partly responsible for the maintaining of the AP plateau (phase 2 of the AP) and involved in the contractile properties of the cardiomyocytes, the slow and rapid components of the delayed rectifier potassium current (I Ks and I Kr ) mainly responsible for the cell late repolarization (phase 3 of the AP), and the inward rectifier potassium current (I K1 ) that helps in the maintenance of the cardiac cell hyperpolarization at rest (phase 4 of the AP). Most of Purkinje fiber studies are conducted in rabbit or dog preparations either because of the high sensitivity of the rabbit cardiac preparation to AP duration variations [22,23] or because comparison of ex vivo and in vivo data (QT interval on dog ECG) are facilitated by use of the same animal species [24,25]. Some scientists claim that the rabbit Purkinje fiber is too much sensitive to AP duration lengthening to be accurately predictive for human and that it would present a high risk of false positive, particularly when Purkinje fibers are removed from females that have been shown as more sensitive than males to such effects [26].…”

Section: Ex Vivo Multicellular Studies On Surrogate Biomarkers Of Promentioning

confidence: 99%

Supplemental Studies for Cardiovascular Risk Assessment in Safety Pharmacology: A Critical Overview

et al. 2011

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Safety Pharmacology studies for the cardiovascular risk assessment, as described in the ICH S7A and S7B guidelines, appear as being far from sufficient. The fact that almost all medicines withdrawn from the market because of life-threatening tachyarrhythmias (torsades-de-pointes) were shown as hERG blockers and QT interval delayers led the authorities to focus mainly on these markers. However, other surrogate biomarkers, e.g., TRIaD (triangulation, reverse-use-dependence, instability and dispersion of ventricular repolarization), have been identified to more accurately estimate the drug-related torsadogenic risk. In addition, more attention should be paid to other arrhythmias, not related to long QT and nevertheless severe and/or not self-extinguishing, e.g., atrial or ventricular fibrillation, resulting from altered electrical conduction or heterogeneous shortening of cardiac repolarization. Moreover, despite numerous clinical cases of drug-induced pulmonary hypertension, orthostatic hypotension, or heart valvular failure, few safety investigations are still conducted on drug interaction with cardiac and regional hemodynamics other than changes in aortic blood pressure evaluated in conscious large animals during the core battery mandatory studies. This critical review aims at discussing the usefulness, relevance, advantages, and limitations of some preclinical in vivo, in vitro, and in silico models, with high predictive values and currently used in supplemental safety studies.

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Evaluation of the Rabbit Purkinje Fibre Assay as an in vitro Tool for Assessing the Risk of Drug-Induced Torsades de Pointes in Humans

Abstract: The rabbit Purkinje fibre is a valuable assay for evaluating the proarrhythmic liability of pharmaceuticals as it can reveal complex electrophysiological profiles that modulate repolarisation delay.

Cited by 40 publications

References 35 publications

Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers

Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers

Principles of Safety Pharmacology

Supplemental Studies for Cardiovascular Risk Assessment in Safety Pharmacology: A Critical Overview

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