Proarrhythmia

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Philip T Sager - One of the best experts on this subject based on the ideXlab platform.

  • comprehensive in vitro Proarrhythmia assay cipa update from a cardiac safety research consortium health and environmental sciences institute fda meeting
    Therapeutic Innovation & Regulatory Science, 2019
    Co-Authors: David G. Strauss, Rick J Turner, Jose Vicente, Gary Gintant, Ksenia Blinova, Philip T Sager
    Abstract:

    A Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA-sponsored Think Tank Meeting was convened in Washington, DC, on May 21, 2018, to bring together scientists, clinicians, and regulators from multiple geographic regions to evaluate progress to date in the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative, a new paradigm to evaluate proarrhythmic risk. Study reports from the 4 different components of the CiPA paradigm (ionic current studies, in silico modeling to generate a Torsade Metric Score, human induced pluripotent stem cell-derived ventricular cardiomyocytes, and clinical ECG assessments including J-Tpeakc) were presented and discussed. This paper provides a high-level summary of the CiPA data presented at the meeting.

  • the comprehensive in vitro Proarrhythmia assay cipa initiative update on progress
    Journal of Pharmacological and Toxicological Methods, 2016
    Co-Authors: Thomas Colatsky, Philip T Sager, Gary Gintant, Jennifer Pierson, David G. Strauss, Bernard Fermini, Yuko Sekino, Norman Stockbridge
    Abstract:

    The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of Proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block. An international multi-disciplinary team of regulatory, industry and academic scientists are working together to develop and validate a set of predominantly nonclinical assays and methods that eliminate the need for the thorough-QT study and enable a more precise prediction of clinical Proarrhythmia risk. The CiPA effort is led by a Steering Team that provides guidance, expertise and oversight to the various working groups and includes partners from US FDA, HESI, CSRC, SPS, EMA, Health Canada, Japan NIHS, and PMDA. The working groups address the three pillars of CiPA that evaluate drug effects on: 1) human ventricular ionic channel currents in heterologous expression systems, 2) in silico integration of cellular electrophysiologic effects based on ionic current effects, the ion channel effects, and 3) fully integrated biological systems (stem-cell-derived cardiac myocytes and the human ECG). This article provides an update on the progress of the initiative towards its target date of December 2017 for completing validation.

  • rechanneling the cardiac Proarrhythmia safety paradigm a meeting report from the cardiac safety research consortium
    American Heart Journal, 2014
    Co-Authors: Philip T Sager, Gary A. Gintant, Rick J Turner, Syril Pettit, Norman Stockbridge
    Abstract:

    This white paper provides a summary of a scientific proposal presented at a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/Food and Drug Administration–sponsored Think Tank, held at Food and Drug Administration's White Oak facilities, Silver Spring, MD, on July 23, 2013, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety in which proarrhythmic risk would be primarily assessed using nonclinical in vitro human models based on solid mechanistic considerations of torsades de pointes Proarrhythmia. This new paradigm would shift the emphasis from the present approach that strongly relies on QTc prolongation (a surrogate marker of Proarrhythmia) and could obviate the clinical Thorough QT study during later drug development. These discussions represent current thinking and suggestions for furthering our knowledge and understanding of the public health case for adopting a new, integrated nonclinical in vitro/in silico paradigm, the Comprehensive In Vitro Proarrhythmia Assay, for the assessment of a candidate drug's proarrhythmic liability, and for developing a public-private collaborative program to characterize the data content, quality, and approaches required to assess proarrhythmic risk in the absence of a Thorough QT study. This paper seeks to encourage multistakeholder input regarding this initiative and does not represent regulatory guidance.

  • clinical evaluation of qt qtc prolongation and proarrhythmic potential for nonantiarrhythmic drugs the international conference on harmonization of technical requirements for registration of pharmaceuticals for human use e14 guideline
    The Journal of Clinical Pharmacology, 2006
    Co-Authors: Borje Darpo, Philip T Sager, Thierry Nebout
    Abstract:

    Proarrhythmias due to drug-induced QT prolongation are the second most common cause for drug withdrawal and have caused increasing concern. Two new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines were recently endorsed in which nonclinical (S7B) and clinical (E14) methodologies are discussed and guidance is given to the industry. This commentary describes the key components of the E14 document, the impact of nonclinical testing on the clinical program, the thorough QT study, and the impact of its result on late-stage development. The studies described in S7B and E14 will contribute to a better understanding of the link between nonclinical assays and QT prolongation in humans. Differences in interpretation among individual regulators in the major regions with respect to measures proposed in the E14 guideline might impact regional regulatory decisions. These differences include the value of nonclinical assays for the subsequent clinical testing and how predictive a negative thorough QT study result is for proarrhythmic risk in patients.

David G. Strauss - One of the best experts on this subject based on the ideXlab platform.

  • comprehensive in vitro Proarrhythmia assay cipa update from a cardiac safety research consortium health and environmental sciences institute fda meeting
    Therapeutic Innovation & Regulatory Science, 2019
    Co-Authors: David G. Strauss, Rick J Turner, Jose Vicente, Gary Gintant, Ksenia Blinova, Philip T Sager
    Abstract:

    A Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA-sponsored Think Tank Meeting was convened in Washington, DC, on May 21, 2018, to bring together scientists, clinicians, and regulators from multiple geographic regions to evaluate progress to date in the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative, a new paradigm to evaluate proarrhythmic risk. Study reports from the 4 different components of the CiPA paradigm (ionic current studies, in silico modeling to generate a Torsade Metric Score, human induced pluripotent stem cell-derived ventricular cardiomyocytes, and clinical ECG assessments including J-Tpeakc) were presented and discussed. This paper provides a high-level summary of the CiPA data presented at the meeting.

  • quantitative systems pharmacology models for a new international cardiac safety regulatory paradigm an overview of the comprehensive in vitro Proarrhythmia assay in silico modeling approach
    CPT: Pharmacometrics & Systems Pharmacology, 2019
    Co-Authors: Christine Garnett, David G. Strauss
    Abstract:

    As a relatively new discipline, quantitative systems pharmacology has seen a significant increase in the application and utility of drug development. One area that could greatly benefit from such an approach is in the Proarrhythmia assessment of new drugs. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative is a global public-private partnership project that has developed an integrated approach using mechanistic in silico models for Proarrhythmia risk prediction. Progress to date has led to the formation of the International Council on Harmonisation Implementation Working Group to revise regulatory guidelines via the Questions-and-Answers process to address the best practices for Proarrhythmia models and how they can impact clinical drug development. This article reviews the CiPA in silico model-development process, focusing on its unique development and validation strategy, and summarizes the lessons learned as consideration points for the ongoing implementation of CiPA-like in silico models in drug development.

  • uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico Proarrhythmia risk assessment
    Frontiers in Physiology, 2017
    Co-Authors: Kelly C Chang, Sara Dutta, Gary R Mirams, Kylie A Beattie, Jiansong Sheng, Phu N Tran, Min Wu, Wendy W Wu, Thomas Colatsky, David G. Strauss
    Abstract:

    The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug Proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the relative risk of drug-induced Torsade de Pointes (TdP) is assessed using an in silico model of the human ventricular action potential (AP) that integrates in vitro pharmacology data from multiple ion channels. Thus, modeling predictions of cardiac risk liability will depend critically on the variability in pharmacology data, and uncertainty quantification (UQ) must comprise an essential component of the in silico assay. This study explores UQ methods that may be incorporated into the CiPA framework. Recently, we proposed a promising in silico TdP risk metric (qNet), which is derived from AP simulations and allows separation of a set of CiPA training compounds into Low, Intermediate, and High TdP risk categories. The purpose of this study was to use UQ to evaluate the robustness of TdP risk separation by qNet. Uncertainty in the model parameters used to describe drug binding and ionic current block was estimated using the non-parametric bootstrap method and a Bayesian inference approach. Uncertainty was then propagated through AP simulations to quantify uncertainty in qNet for each drug. UQ revealed lower uncertainty and more accurate TdP risk stratification by qNet when simulations were run at concentrations below 5× the maximum therapeutic exposure (Cmax). However, when drug effects were extrapolated above 10× Cmax, UQ showed that qNet could no longer clearly separate drugs by TdP risk. This was because for most of the pharmacology data, the amount of current block measured was <60%, preventing reliable estimation of IC50-values. The results of this study demonstrate that the accuracy of TdP risk prediction depends both on the intrinsic variability in ion channel pharmacology data as well as on experimental design considerations that preclude an accurate determination of drug IC50-values in vitro. Thus, we demonstrate that UQ provides valuable information about in silico modeling predictions that can inform future proarrhythmic risk evaluation of drugs under the CiPA paradigm.

  • the comprehensive in vitro Proarrhythmia assay cipa initiative update on progress
    Journal of Pharmacological and Toxicological Methods, 2016
    Co-Authors: Thomas Colatsky, Philip T Sager, Gary Gintant, Jennifer Pierson, David G. Strauss, Bernard Fermini, Yuko Sekino, Norman Stockbridge
    Abstract:

    The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of Proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block. An international multi-disciplinary team of regulatory, industry and academic scientists are working together to develop and validate a set of predominantly nonclinical assays and methods that eliminate the need for the thorough-QT study and enable a more precise prediction of clinical Proarrhythmia risk. The CiPA effort is led by a Steering Team that provides guidance, expertise and oversight to the various working groups and includes partners from US FDA, HESI, CSRC, SPS, EMA, Health Canada, Japan NIHS, and PMDA. The working groups address the three pillars of CiPA that evaluate drug effects on: 1) human ventricular ionic channel currents in heterologous expression systems, 2) in silico integration of cellular electrophysiologic effects based on ionic current effects, the ion channel effects, and 3) fully integrated biological systems (stem-cell-derived cardiac myocytes and the human ECG). This article provides an update on the progress of the initiative towards its target date of December 2017 for completing validation.

Jeanpierre Valentin - One of the best experts on this subject based on the ideXlab platform.

  • Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia assay cipa an industry survey on current practice
    Journal of Pharmacological and Toxicological Methods, 2017
    Co-Authors: Simon Authier, Jeanpierre Valentin, Michael K Pugsley, Derek J Leishman, Bernard Fermini, Krystle Correll, John Koerner, William S Redfern, Hugo M Vargas, Michael J Curtis
    Abstract:

    Abstract Introduction The Safety Pharmacology Society (SPS) has conducted a survey of its membership to identify industry practices related to testing considered in the Comprehensive In vitro Proarrhythmia Assay (CiPA). Methods Survey topics included nonclinical approaches to address Proarrhythmia issues, conduct of in silico studies, in vitro ion channel testing methods used, drugs used as positive controls during the conduct of cardiac ion channel studies, types of arrhythmias observed in non-clinical studies and use of the anticipated CiPA ion channel assay. Results In silico studies were used to evaluate effects on ventricular action potentials by only 15% of responders. In vitro assays were used mostly to assess QT prolongation (95%), cardiac Ca2 + and Na+ channel blockade (82%) and QT shortening or QRS prolongation (53%). For de-risking of candidate drugs for Proarrhythmia, those assays most relevant to CiPA including cell lines stably expressing ion channels used to determine potency of drug block were most frequently used (89%) and human stem cell-derived or induced pluripotent stem cell cardiomyocytes (46%). Those in vivo assays related to general Proarrhythmia derisking include ECG recording using implanted telemetry technology (88%), jacketed external telemetry (62%) and anesthetized animal models (53%). While the CiPA initiative was supported by 92% of responders, there may be some disconnect between current practice and future expectations, as explained. Discussion 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.

  • dog left ventricular midmyocardial myocytes for assessment of drug induced delayed repolarization short term variability and proarrhythmic potential
    British Journal of Pharmacology, 2010
    Co-Authors: Najah Abigerges, Jeanpierre Valentin, C E Pollard
    Abstract:

    Background and purpose:  Evaluation of the potential for delayed ventricular repolarization and Proarrhythmia by new drugs is essential. We investigated if dog left ventricular midmyocardial myocytes (LVMMs) that can be used as a preclinical model to assess drug effects on action potential duration (APD) and whether in these cells, short-term variability (STV) or triangulation could predict proarrhythmic potential. Experimental approach:  Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD50) and 90% (APD90) of repolarization, STV(APD), triangulation (ratio APD90/APD50) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz. Key results:  LVMMs provided stable recordings of AP, which were not affected by four sequential additions of dimethyl sulphoxide. Effects of dofetilide, d-sotalol, cisapride, pinacidil and diltiazem, but not of terfenadine, on APD in LVMMs were found to be comparable with those recorded in PFs. LVMMs, but not PFs, exhibited a proarrhythmic response to IKr blockers. Incidence of EADs was not related to differences in AP prolongation or triangulation, but corresponded to beat-to-beat variability of repolarization, here quantified as STV of APD. Conclusions and implications:  LVMMs provide a suitable preclinical model to assess the effects of new drugs on APD and also yield additional information about putative indicators of Proarrhythmia that add value to an integrated QT/TdP risk assessment. Our findings support the concept that increased STV(APD) may predict drug-induced Proarrhythmia. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010

  • in vitro models of Proarrhythmia
    British Journal of Pharmacology, 2008
    Co-Authors: Chris L Lawrence, Chris E Pollard, Tim G Hammond, Jeanpierre Valentin
    Abstract:

    Proarrhythmia models use electrophysiological markers to predict the risk of torsade de pointes (TdP) in patients. The set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome; however, these reports should be interpreted cautiously as no model has been independently assessed. Each model is discussed along with its merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. As predictive as these models may become, extrapolation of results directly to the clinic must be exercised with caution. The use of in silico models, from subcellular to whole system, is rapidly beginning to form the first line of screening activity in many drug discovery programmes, indicating that biological experimentation may become secondary to analysis by simulation. In vitro Proarrhythmia models challenge current perceptions of appropriate surrogates for TdP in man and question existing non-clinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of Proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key Proarrhythmia mechanisms. With greater acceptance and ongoing improvements, these models have the potential to unravel the complex mechanisms underlying TdP.

  • a rabbit langendorff heart Proarrhythmia model predictive value for clinical identification of torsades de pointes
    British Journal of Pharmacology, 2006
    Co-Authors: C.l. Lawrence, Matthew Bridglandtaylor, C E Pollard, Tim Hammond, Jeanpierre Valentin
    Abstract:

    Background and purpose: The rabbit isolated Langendorff heart model (SCREENIT) was used to investigate the proarrhythmic potential of a range of marketed drugs or drugs intended for market. These data were used to validate the SCREENIT model against clinical outcomes. Experimental approach: Fifty-five drugs, 3 replicates and 2 controls were tested in a blinded manner. Proarrhythmia variables included a 10% change in MAPD60, triangulation, instability and reverse frequency-dependence of the MAP. Early afterdepolarisations, ventricular tachycardia, TdP and ventricular fibrillation were noted. Data are reported at nominal concentrations relative to EFTPCmax. Proarrhythmic scores were assigned to each drug and each drug category. Key results: Category 1 and 2 drugs have the highest number of Proarrhythmia variables and overt Proarrhythmia while Category 5 drugs have the lowest, at every margin. At 30-fold the EFTPCmax, the mean proarrhythmic scores are: Category 1, 101724; Category 2, 101714; Category 3, 72720; Category 4, 59716 and Category 5, 2279 points. Only drugs in Category 5 have mean proarrhythmic scores, below 30-fold, that remain within the Safety Zone. Conclusions and Implications: A 30-fold margin between effects and EFTPCmax is sufficiently stringent to provide confidence to proceed with a new chemical entity, without incurring the risk of eliminating potentially beneficial drugs. The model is particularly useful where compounds have small margins between the hERG IC50 and predicted EFTPCmax. These data suggest this is a robust and reliable assay that can add value to an integrated QT/TdP risk assessment. British Journal of Pharmacology (2006) 149, 845–860. doi:10.1038/sj.bjp.0706894; published online 9 October 2006

  • nonclinical Proarrhythmia models predicting torsades de pointes
    Journal of Pharmacological and Toxicological Methods, 2005
    Co-Authors: Chris L Lawrence, Chris E Pollard, Tim G Hammond, Jeanpierre Valentin
    Abstract:

    Prolongation of the QT interval and the cardiac action potential have been linked to a potentially fatal but rare tachyarrhythmia known as Torsades de Pointes (TdP). Nonclinical assays, such as those investigating the effect on I(Kr) (the hERG channel current), prolongation of the action potential duration (APD) and the QT interval, in vivo, have been developed to predict the risk of QT interval prolongation and TdP in man. However, there seems to be a dissociation between the risk of QT interval prolongation and the torsadogenic risk. There is an increasing mass of evidence showing that an increase in the QT interval does not necessarily lead to TdP. Thus, it appears that while standard assays are very good, although perhaps not infallible, at predicting the risk of QT interval prolongation in man they do not predict the proarrhythmic risk. Recently there has been a plethora of publications suggesting that there are electrophysiological markers associated with drug-induced TdP other than hERG channel activity, APD and the QT interval, and these markers may be better predictors of TdP. In this review, three in vitro and, briefly, three in vivo models or methods are discussed. These Proarrhythmia models use electrophysiological markers such as transmural dispersion of repolarization, action potential triangulation, instability, reverse use-dependence, and the incidence of early after-depolarizations to predict the risk of TdP. Most of the models presented have been published widely. The particular variable or set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome. While each variable/model has been shown to discriminate between antiarrhythmic and nonarrhythmic drugs, these reports should be interpreted cautiously since none has been independently (externally) assessed. Each model is discussed along with its particular merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. Proarrhythmia models, in particular in vitro models, challenge current perceptions of appropriate surrogates for TdP in man and question existing nonclinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of Proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key Proarrhythmia mechanisms. Regardless of regulatory acceptance, with further validation these models may still enhance pharmaceutical company decision-making to provide a rational basis for drug progression, particularly in areas of unmet medical need.

Henry Holzgrefe - One of the best experts on this subject based on the ideXlab platform.

  • the prospective iq csrc trial a prototype early clinical Proarrhythmia assessment investigation for replacing the ich e14 thorough qtc tqt study
    Journal of Pharmacological and Toxicological Methods, 2016
    Co-Authors: Icilio Cavero, Henry Holzgrefe, Mike Clements
    Abstract:

    Abstract Introduction Early clinical Phase I ECG investigations designed to replace the currently applied thorough QT (TQT) study are reviewed to examine how they could complement and verify the conclusions of nonclinical investigations and, in particular, the Comprehensive in vitro Proarrhythmia Assay (CiPA). Topics The IQ-CSRC trial is a prospective ascending multiple-dose first in human (FIH) type investigation performed as a possible replacement for the thorough QT study (TQT). Designed in accordance with the results of a simulation study by the FDA QT Interdisciplinary Review Team (IRT), it succeeded in correctly categorizing 5/5 established QTc-prolonging agents free of notable heart rate effects (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and the QTc-negative drug, levocetirizine. Discussion The positive results obtained with the IQ-CSRC study require additional confirmation with threshold QTc-positive and negative drugs and established QTc prolongers producing both increases and decreases in heart rate. In the future, similar studies should also adopt and validate innovative proarrhythmic metrics, in addition to, or instead of, the traditional proarrhythmic surrogate of QTc, to assess the proarrhythmic safety of candidate drugs.

  • Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation
    Journal of Pharmacological and Toxicological Methods, 2016
    Co-Authors: Icilio Cavero, Jean-michel Guillon, Veronique Ballet, Mike Clements, Jean-frédéric Gerbeau, Henry Holzgrefe
    Abstract:

    Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer proarrhythmic liability to drug candidates intended for human use. Topics covered: Key talks delivered at the ‘CiPA on my mind’ session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e.g., biological materials (ion channels and pluripotent stem cell-derived cardiomyocytes), study platforms, drug solutions, and data analysis] of CiPA core assays are critically examined. Discussion: In order to advance the CiPA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by CiPA stakeholders is necessary to expedite solutions to pending and newly arising issues. Once a study protocol is proved to yield robust and reproducible results within and across laboratories, it can be implemented as qualified regulatory procedure.

  • comprehensive in vitro Proarrhythmia assay a novel in vitro in silico paradigm to detect ventricular proarrhythmic liability a visionary 21st century initiative
    Expert Opinion on Drug Safety, 2014
    Co-Authors: Icilio Cavero, Henry Holzgrefe
    Abstract:

    Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a novel safety screening proposal intended to replace the 2005 regulatory strategy recommended by the International Conference of Harmonization S7B guideline. Areas covered: CiPA consists of three components. The first assay evaluates candidate drug effects on key cardiac ion channels. Then, simulations test whether the channel dataset yields proarrhythmic markers on a computationally reconstructed human ventricular cardiomyocyte action potential. Finally, the relevance of in silico conclusions is verified by determining the electrical activity of human stem cell-derived ventricular cardiomyocytes. Expert opinion: The CiPA initiative is intended to move safety pharmacology from a predominantly traditional pharmacodynamics approach to in silico and in vitro drug toxicity assessment. In practice, CiPA assays will have to be compliant with regulatory safety pharmacology tenets. The latter will necessitate international consensus on assay ...

Bernard Fermini - One of the best experts on this subject based on the ideXlab platform.

  • Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia assay cipa an industry survey on current practice
    Journal of Pharmacological and Toxicological Methods, 2017
    Co-Authors: Simon Authier, Jeanpierre Valentin, Michael K Pugsley, Derek J Leishman, Bernard Fermini, Krystle Correll, John Koerner, William S Redfern, Hugo M Vargas, Michael J Curtis
    Abstract:

    Abstract Introduction The Safety Pharmacology Society (SPS) has conducted a survey of its membership to identify industry practices related to testing considered in the Comprehensive In vitro Proarrhythmia Assay (CiPA). Methods Survey topics included nonclinical approaches to address Proarrhythmia issues, conduct of in silico studies, in vitro ion channel testing methods used, drugs used as positive controls during the conduct of cardiac ion channel studies, types of arrhythmias observed in non-clinical studies and use of the anticipated CiPA ion channel assay. Results In silico studies were used to evaluate effects on ventricular action potentials by only 15% of responders. In vitro assays were used mostly to assess QT prolongation (95%), cardiac Ca2 + and Na+ channel blockade (82%) and QT shortening or QRS prolongation (53%). For de-risking of candidate drugs for Proarrhythmia, those assays most relevant to CiPA including cell lines stably expressing ion channels used to determine potency of drug block were most frequently used (89%) and human stem cell-derived or induced pluripotent stem cell cardiomyocytes (46%). Those in vivo assays related to general Proarrhythmia derisking include ECG recording using implanted telemetry technology (88%), jacketed external telemetry (62%) and anesthetized animal models (53%). While the CiPA initiative was supported by 92% of responders, there may be some disconnect between current practice and future expectations, as explained. Discussion 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.

  • the comprehensive in vitro Proarrhythmia assay cipa initiative update on progress
    Journal of Pharmacological and Toxicological Methods, 2016
    Co-Authors: Thomas Colatsky, Philip T Sager, Gary Gintant, Jennifer Pierson, David G. Strauss, Bernard Fermini, Yuko Sekino, Norman Stockbridge
    Abstract:

    The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of Proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block. An international multi-disciplinary team of regulatory, industry and academic scientists are working together to develop and validate a set of predominantly nonclinical assays and methods that eliminate the need for the thorough-QT study and enable a more precise prediction of clinical Proarrhythmia risk. The CiPA effort is led by a Steering Team that provides guidance, expertise and oversight to the various working groups and includes partners from US FDA, HESI, CSRC, SPS, EMA, Health Canada, Japan NIHS, and PMDA. The working groups address the three pillars of CiPA that evaluate drug effects on: 1) human ventricular ionic channel currents in heterologous expression systems, 2) in silico integration of cellular electrophysiologic effects based on ionic current effects, the ion channel effects, and 3) fully integrated biological systems (stem-cell-derived cardiac myocytes and the human ECG). This article provides an update on the progress of the initiative towards its target date of December 2017 for completing validation.

  • a new perspective in the field of cardiac safety testing through the comprehensive in vitro Proarrhythmia assay paradigm
    Journal of Biomolecular Screening, 2016
    Co-Authors: Bernard Fermini, Matthew Bridglandtaylor, Najah Abigerges, Thomas Colatsky, Jules C Hancox, Khuram W Chaudhary, Krystle Correll, William Crumb, Bruce P Damiano, Gul Erdemli
    Abstract:

    For the past decade, cardiac safety screening to evaluate the propensity of drugs to produce QT interval prolongation and Torsades de Pointes (TdP) arrhythmia has been conducted according to ICH S7B and ICH E14 guidelines. Central to the existing approach are hERG channel assays and in vivo QT measurements. Although effective, the present paradigm carries a risk of unnecessary compound attrition and high cost, especially when considering costly thorough QT (TQT) studies conducted later in drug development. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative is a public-private collaboration with the aim of updating the existing cardiac safety testing paradigm to better evaluate arrhythmia risk and remove the need for TQT studies. It is hoped that CiPA will produce a standardized ion channel assay approach, incorporating defined tests against major cardiac ion channels, the results of which then inform evaluation of proarrhythmic actions in silico, using human ventricular action potential reco...

  • a new perspective in the field of cardiac safety testing through the comprehensive in vitro Proarrhythmia assay paradigm
    Journal of Biomolecular Screening, 2016
    Co-Authors: Bernard Fermini, Matthew Bridglandtaylor, Najah Abigerges, Thomas Colatsky, Jules C Hancox, Khuram W Chaudhary, Krystle Correll, William Crumb, Bruce P Damiano, Gul Erdemli
    Abstract:

    For the past decade, cardiac safety screening to evaluate the propensity of drugs to produce QT interval prolongation and Torsades de Pointes (TdP) arrhythmia has been conducted according to ICH S7B and ICH E14 guidelines. Central to the existing approach are hERG channel assays and in vivo QT measurements. Although effective, the present paradigm carries a risk of unnecessary compound attrition and high cost, especially when considering costly thorough QT (TQT) studies conducted later in drug development. The C: omprehensive I: n Vitro P: roarrhythmia A: ssay (CiPA) initiative is a public-private collaboration with the aim of updating the existing cardiac safety testing paradigm to better evaluate arrhythmia risk and remove the need for TQT studies. It is hoped that CiPA will produce a standardized ion channel assay approach, incorporating defined tests against major cardiac ion channels, the results of which then inform evaluation of proarrhythmic actions in silico, using human ventricular action potential reconstructions. Results are then to be confirmed using human (stem cell-derived) cardiomyocytes. This perspective article reviews the rationale, progress of, and challenges for the CiPA initiative, if this new paradigm is to replace existing practice and, in time, lead to improved and widely accepted cardiac safety testing guidelines.