The Experts below are selected from a list of 14064 Experts worldwide ranked by ideXlab platform
Mark R Davies - One of the best experts on this subject based on the ideXlab platform.
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A new classifier-based strategy for in-silico ion-channel cardiac Drug Safety Assessment.
Frontiers in pharmacology, 2015Co-Authors: Hitesh Mistry, Mark R Davies, Giovanni Y Di VeroliAbstract:There is currently a strong interest in using high-throughput in-vitro ion-channel screening data to make predictions regarding the cardiac toxicity potential of a new compound in both animal and human studies. A recent FDA think tank encourages the use of biophysical mathematical models of cardiac myocytes for this prediction task. However, it remains unclear whether this approach is the most appropriate. Here we examine five literature data-sets that have been used to support the use of four different biophysical models and one statistical model for predicting cardiac toxicity in numerous species using various endpoints. We propose a simple model that represents the balance between repolarisation and depolarisation forces and compare the predictive power of the model against the original results (leave-one-out cross-validation). Our model showed equivalent performance when compared to the four biophysical models and one statistical model. We therefore conclude that this approach should be further investigated in the context of early cardiac Safety screening when in-vitro potency data is generated.
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herg inhibitors with similar potency but different binding kinetics do not pose the same proarrhythmic risk implications for Drug Safety Assessment
Journal of Cardiovascular Electrophysiology, 2014Co-Authors: Mark R Davies, Giovanni Y Di Veroli, Henggui Zhang, Najah Abigerges, F Mark R C P R BoyettAbstract:INTRODUCTION: Since the discovery of the link that exists between Drug-induced hERG inhibition and Torsade de Pointes (TdP), extreme attention has been given to avoid new Drugs inhibiting this channel. hERG inhibition is routinely screened for in new Drugs and, typically, IC50 values are compared to projected plasma concentrations to define a Safety margin. METHODS AND RESULTS: We aimed to show that Drugs with similar hERG potency are not uniformly pro-arrhythmic-this depends on the Drug binding kinetics and mode of action (trapped or not) rather than the IC50 value only. We used a mathematical model of hERG and its related encoded current IKr to simulate Drug binding in different configurations. Expression systems mimicking the screening process were first investigated. hERG model was then incorporated into a canine action potential (AP) and tissue model to study the impact of Drug binding configurations on AP and pseudo-ECG (QT interval prolongation). Our data show that: (1) trapped and not trapped configurations and different binding kinetics could be identified during hERG screening; (2) slow binding, not trapped Drugs, induced less AP prolongation and minimal QT interval prolongation (4.7%) at a concentration equal to the IC50 whereas maximal pro-arrhythmic risk was observed for trapped Drugs at the same concentration (QT interval prolongation, 23.1%). CONCLUSION: Our study demonstrates the need for screening for hERG binding configurations rather than potency alone. It also demonstrates the potential link between hERG, Drug mode of action and TdP, and the need to question the current regulatory guidance.
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high throughput screening of Drug binding dynamics to herg improves early Drug Safety Assessment
American Journal of Physiology-heart and Circulatory Physiology, 2013Co-Authors: Mark R Davies, Giovanni Y Di Veroli, Henggui Zhang, Najah Abigerges, Mark R BoyettAbstract:The use of computational models to predict Drug-induced changes in the action potential (AP) is a promising approach to reduce Drug Safety attrition but requires a better representation of more complex Drug-target interactions to improve the quantitative prediction. The blockade of the human ether-a-go-go-related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk. We aim to develop quantitative in-silico AP predictions based on a new electrophysiological protocol (suitable for high-throughput HERG screening) and mathematical modeling of ionic currents. Electrophysiological recordings using the IonWorks device were made from HERG channels stably expressed in Chinese hamster ovary cells. A new protocol that delineates inhibition over time was applied to assess dofetilide, cisapride, and almokalant effects. Dynamic effects displayed distinct profiles for these Drugs compared with concentration-effects curves. Binding kinetics to specific states were identified using a new ...
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High-throughput screening of Drug-binding dynamics to HERG improves early Drug Safety Assessment
American journal of physiology. Heart and circulatory physiology, 2012Co-Authors: Giovanni Y Di Veroli, Mark R Davies, Najah Abi-gerges, Henggui Zhang, Mark R BoyettAbstract:The use of computational models to predict Drug-induced changes in the action potential (AP) is a promising approach to reduce Drug Safety attrition but requires a better representation of more com...
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an in silico canine cardiac midmyocardial action potential duration model as a tool for early Drug Safety Assessment
American Journal of Physiology-heart and Circulatory Physiology, 2012Co-Authors: Mark R Davies, Hitesh Mistry, Chris E Pollard, Jonathan Swinton, L Hussein, Jeanpierre Valentin, Najah AbigergesAbstract:Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT Assessment....
Jochen Koenig - One of the best experts on this subject based on the ideXlab platform.
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Omic profiling for Drug Safety Assessment: current trends and public–private partnerships
Drug Discovery Today, 2009Co-Authors: William M Gallagher, David Tweats, Jochen KoenigAbstract:The Drug development process is currently being hindered by non-optimal prediction of toxicity. Advances in molecular profiling approaches, such as transcriptomics, proteomics and metabolomics, offer the potential to provide a more comprehensive insight into toxicological effects than hitherto possible. These new technologies present their own challenges, however, particularly in relation to standardization and Assessment. The focus of this article is on describing the current trends concerning the application of omic approaches in Drug Safety Assessment, with specific emphasis on the role of public-private partnerships in advancing this emerging arena.
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Omic profiling for Drug Safety Assessment: current trends and public-private partnerships.
Drug discovery today, 2009Co-Authors: William M Gallagher, David Tweats, Jochen KoenigAbstract:The Drug development process is currently being hindered by non-optimal prediction of toxicity. Advances in molecular profiling approaches, such as transcriptomics, proteomics and metabolomics, offer the potential to provide a more comprehensive insight into toxicological effects than hitherto possible. These new technologies present their own challenges, however, particularly in relation to standardization and Assessment. The focus of this article is on describing the current trends concerning the application of omic approaches in Drug Safety Assessment, with specific emphasis on the role of public-private partnerships in advancing this emerging arena.
Panuwat Trairatphisan - One of the best experts on this subject based on the ideXlab platform.
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quantitative systems toxicology modeling to address key Safety questions in Drug development a focus of the transqst consortium
Chemical Research in Toxicology, 2020Co-Authors: Sofia Ferreira, Ciaran Fisher, Laura I Furlong, Loic Laplanche, B K Park, Julio Saezrodriguez, Panuwat TrairatphisanAbstract:Omics data have been increasingly generated with limited demonstrated value in Drug Safety Assessment. The TransQST consortium was launched to use omics and other data in mechanistic-based quantita...
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Quantitative Systems Toxicology Modeling To Address Key Safety Questions in Drug Development: A Focus of the TransQST Consortium.
Chemical research in toxicology, 2020Co-Authors: Sofia Ferreira, Ciaran Fisher, Laura I Furlong, Loic Laplanche, B K Park, Carmen Pin, Julio Saez-rodriguez, Panuwat TrairatphisanAbstract:Omics data have been increasingly generated with limited demonstrated value in Drug Safety Assessment. The TransQST consortium was launched to use omics and other data in mechanistic-based quantitative systems toxicology (QST) models to evaluate their potential use in species translation.
Giovanni Y Di Veroli - One of the best experts on this subject based on the ideXlab platform.
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A new classifier-based strategy for in-silico ion-channel cardiac Drug Safety Assessment.
Frontiers in pharmacology, 2015Co-Authors: Hitesh Mistry, Mark R Davies, Giovanni Y Di VeroliAbstract:There is currently a strong interest in using high-throughput in-vitro ion-channel screening data to make predictions regarding the cardiac toxicity potential of a new compound in both animal and human studies. A recent FDA think tank encourages the use of biophysical mathematical models of cardiac myocytes for this prediction task. However, it remains unclear whether this approach is the most appropriate. Here we examine five literature data-sets that have been used to support the use of four different biophysical models and one statistical model for predicting cardiac toxicity in numerous species using various endpoints. We propose a simple model that represents the balance between repolarisation and depolarisation forces and compare the predictive power of the model against the original results (leave-one-out cross-validation). Our model showed equivalent performance when compared to the four biophysical models and one statistical model. We therefore conclude that this approach should be further investigated in the context of early cardiac Safety screening when in-vitro potency data is generated.
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herg inhibitors with similar potency but different binding kinetics do not pose the same proarrhythmic risk implications for Drug Safety Assessment
Journal of Cardiovascular Electrophysiology, 2014Co-Authors: Mark R Davies, Giovanni Y Di Veroli, Henggui Zhang, Najah Abigerges, F Mark R C P R BoyettAbstract:INTRODUCTION: Since the discovery of the link that exists between Drug-induced hERG inhibition and Torsade de Pointes (TdP), extreme attention has been given to avoid new Drugs inhibiting this channel. hERG inhibition is routinely screened for in new Drugs and, typically, IC50 values are compared to projected plasma concentrations to define a Safety margin. METHODS AND RESULTS: We aimed to show that Drugs with similar hERG potency are not uniformly pro-arrhythmic-this depends on the Drug binding kinetics and mode of action (trapped or not) rather than the IC50 value only. We used a mathematical model of hERG and its related encoded current IKr to simulate Drug binding in different configurations. Expression systems mimicking the screening process were first investigated. hERG model was then incorporated into a canine action potential (AP) and tissue model to study the impact of Drug binding configurations on AP and pseudo-ECG (QT interval prolongation). Our data show that: (1) trapped and not trapped configurations and different binding kinetics could be identified during hERG screening; (2) slow binding, not trapped Drugs, induced less AP prolongation and minimal QT interval prolongation (4.7%) at a concentration equal to the IC50 whereas maximal pro-arrhythmic risk was observed for trapped Drugs at the same concentration (QT interval prolongation, 23.1%). CONCLUSION: Our study demonstrates the need for screening for hERG binding configurations rather than potency alone. It also demonstrates the potential link between hERG, Drug mode of action and TdP, and the need to question the current regulatory guidance.
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high throughput screening of Drug binding dynamics to herg improves early Drug Safety Assessment
American Journal of Physiology-heart and Circulatory Physiology, 2013Co-Authors: Mark R Davies, Giovanni Y Di Veroli, Henggui Zhang, Najah Abigerges, Mark R BoyettAbstract:The use of computational models to predict Drug-induced changes in the action potential (AP) is a promising approach to reduce Drug Safety attrition but requires a better representation of more complex Drug-target interactions to improve the quantitative prediction. The blockade of the human ether-a-go-go-related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk. We aim to develop quantitative in-silico AP predictions based on a new electrophysiological protocol (suitable for high-throughput HERG screening) and mathematical modeling of ionic currents. Electrophysiological recordings using the IonWorks device were made from HERG channels stably expressed in Chinese hamster ovary cells. A new protocol that delineates inhibition over time was applied to assess dofetilide, cisapride, and almokalant effects. Dynamic effects displayed distinct profiles for these Drugs compared with concentration-effects curves. Binding kinetics to specific states were identified using a new ...
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High-throughput screening of Drug-binding dynamics to HERG improves early Drug Safety Assessment
American journal of physiology. Heart and circulatory physiology, 2012Co-Authors: Giovanni Y Di Veroli, Mark R Davies, Najah Abi-gerges, Henggui Zhang, Mark R BoyettAbstract:The use of computational models to predict Drug-induced changes in the action potential (AP) is a promising approach to reduce Drug Safety attrition but requires a better representation of more com...
Michael J Curtis - One of the best experts on this subject based on the ideXlab platform.
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Back to the future: Safety pharmacology methods and models in 2013
Journal of Pharmacological and Toxicological Methods, 2013Co-Authors: Michael K. Pugsley, Simon Authier, Michael J CurtisAbstract:Abstract Safety pharmacology continues to seek to validate and refine methods for use in preclinical detection of adverse effect liability. Almost uniquely in pharmacology, Drug Safety Assessment by Safety pharmacologists is driven by the need for elaboration and validation of methods for detecting Drug actions. This is the 10th consecutive year that the Journal of Pharmacological and Toxicological Methods (JPTM) has published themed issues arising from the annual meeting of the Safety Pharmacology Society (SPS), most recently held in Phoenix, AZ in 2012. The SPS is now into its 13th year as a distinct (from Pharmacology and Toxicology) discipline that integrates Safety pharmacologists from industry with those in academia and the various global regulatory authorities. Some of the unique sessions of the 2012 meeting included (i) Oncology Therapies, (ii) Assessment of Cardiac Function and (iii) The Growing Role of Safety Pharmacology. This issue of JPTM reflects these themes. As with the previous 10 issues of the Journal , the manuscripts in this issue encompass a broad spectrum of Safety pharmacology topics including application of state-of-the-art methods in keeping with the directive of the ICH S7A guidance document emphasizing “…the use of new technologies and methodologies in accordance with sound scientific principles…” study conduct and data analysis, processing and evaluation. This includes some exciting new applications with well validated in vitro and ex vivo Safety pharmacology models, refinements in high throughput screening methods with application for use in early Safety pharmacology Assessments, modified supplemental Safety methods meant to evaluate potential adverse pharmacodynamic effects on organ system functions not addressed by the core battery and heart rate variability in non-human primates (NHP). Additionally a series of fascinating articles examining the effects of known Drugs on electrophysiological and contractile function in human induced (iPSC-CM) and embryonic (hESC-CM) stem cells are presented. A historical review on hERG channel electrophysiology and channel characterization, efforts of the HESI Cardiac Technical Safety Committee since its inception and an overview of the dynamic and vibrant Safety Pharmacology Society (SPS) are also included in this issue.
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Methodological innovations expand the Safety pharmacology horizon.
Journal of Pharmacological and Toxicological Methods, 2012Co-Authors: Michael K. Pugsley, Michael J CurtisAbstract:Abstract Almost uniquely in pharmacology, Drug Safety Assessment is driven by the need for elaboration and validation of methods for detecting Drug actions. This is the 9th consecutive year that the Journal of Pharmacological and Toxicological Methods (JPTM) has published themed issues arising from the annual meeting of the Safety Pharmacology Society (SPS). The SPS is now past its 10th year as a distinct (from pharmacology to toxicology) discipline that integrates Safety pharmacologists from industry with those in academia and the various global regulatory authorities. The themes of the 2011 meeting were (i) the bridging of Safety Assessment of a new chemical entity (NCE) between all the parties involved, (ii) applied technologies and (iii) translation. This issue of JPTM reflects these themes. The content is informed by the regulatory guidance documents (S7A and S7B) that apply prior to first in human (FIH) studies, which emphasize the importance of seeking model validation. The manuscripts encompass a broad spectrum of Safety pharmacology topics including application of state-of-the-art techniques for study conduct and data processing and evaluation. This includes some exciting novel integrated core battery study designs, refinements in hemodynamic Assessment, arrhythmia analysis algorithms, and additionally an overview of Safety immunopharmacology, and a brief survey discussing similarities and differences in business models that pharmaceutical companies employ in Safety pharmacology, together with SPS recommendations on ‘best practice’ for the conduct of a non-clinical cardiovascular Assessment of a NCE.
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Non-clinical models: Validation, study design and statistical consideration in Safety pharmacology
Journal of Pharmacological and Toxicological Methods, 2010Co-Authors: Michael K. Pugsley, Simon Authier, Rob Towart, David J. Gallacher, Michael J CurtisAbstract:The current issue of the Journal of Pharmacological and Toxicological Methods (JPTM) focuses exclusively on Safety pharmacology methods. This is the 7th year the Journal has published on this topic. Methods and models that specifically relate to methods relating to the Assessment of the Safety profile of a new chemical entity (NCE) prior to first in human (FIH) studies are described. Since the Journal started publishing on this topic there has been a major effort by Safety pharmacologists, toxicologists and regulatory scientists within Industry (both large and small Pharma as well as Biotechnology companies) and also from Contract Research Organizations (CRO) to publish the surgical details of the non-clinical methods utilized but also provide important details related to standard and non-standard (or integrated) study models and designs. These details from core battery and secondary (or ancillary) Drug Safety Assessment methods used in Drug development programs have been the focus of these special issues and have been an attempt to provide validation of methods. Similarly, the Safety pharmacology issues of the Journal provide the most relevant forum for scientists to present novel and modified methods with direct applicability to determination of Drug Safety—directly to the Safety pharmacology scientific community. The content of the manuscripts in this issue includes the introduction of additional important surgical methods, novel data capture and data analysis methods, improved study design and effects of positive control compounds with known activity in the model.
