Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart

Bottino, Dean; Penland, Robert C.; Stamps, Andrew T.; Traebert, Martin; Dumotier, Bérengère; Georgieva, Anna; Helmlinger, Gabriel; Lett, G.

doi:10.1016/j.pbiomolbio.2005.06.006

Cited by 66 publications

(49 citation statements)

References 80 publications

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“…For example, a model was developed to quantitatively predict the degree of sodium channel blockade required to offset the effects of a hERG channel blocker on action potential prolongation in canine Purkinje fibers (Bottino et al, 2006). The estimated IC 50 values for hNav1.5 inhibition were subsequently confirmed with data from independent patch-clamp experiments (Bottino et al, 2006).…”

Section: Pre-clinical Assessmentmentioning

confidence: 99%

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Erdemli¹,

Kim²,

Ju³

et al. 2012

Front. Pharmacol.

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The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene) is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection, and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a pre-clinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development.

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Section: Pre-clinical Assessmentmentioning

confidence: 99%

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Erdemli¹,

Kim²,

Ju³

et al. 2012

Front. Pharmacol.

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“…Computational models have been developed more recently to scrutinize the potential proarrhythmic risk of drugs on the single hERG channel [55], on the cardiac AP, [56] or on the cell electrical propagation at the tissue level [57][58][59]. In silico models on hERG channel-drug interactions have been set up with a 3D quantitative structureactivity relationship (QSAR).…”

Section: In Vitro Channel Studies and In Silico Modelsmentioning

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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“…In Bottino et al (2006), a combined forward and reverse engineering approach was used to reconcile the inhibition of hERG channel (IC 50 -values in micromolar range) with the lack of prolongation of action potential (AP) duration recorded from canine Purkinje fibers (PF) with two compounds. First, a computational model of canine PF was constructed from a model of canine ventricular myocytes (Greenstein and Winslow, 2002) using reverse engineering.…”

Section: The Notion Of Reverse and Forward Engineeringmentioning

confidence: 99%

Preclinical cardio-safety assessment of torsadogenic risk and alternative methods to animal experimentation: The inseparable twins

Dumotier

Georgieva²

2007

Cell Biol Toxicol

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The last decade has been marked by the withdrawal from the market of several medicines whose use in patients has been associated with the development of torsade de pointes (TdP), a potentially life-threatening polymorphic tachycardia. In a few cases, TdP can degenerate into ventricular fibrillation and lead to sudden death, thus constituting a real problem of public health. The recently finalized ICH S7B guideline defines the prolongation of the QT interval on the electrocardiogram as the best biomarker for predicting the torsadogenic risk of a given compound. However, a growing body of evidence suggests that drugs' torsadogenic potential may not necessarily be proportional to their ability to prolong the QT interval. It is a dynamic combination of multiple predisposing factors and components rather than a single particular event that can trigger this particular tachycardia. Following recommendations of the guideline, pharmaceutical companies have intensively implemented methodologies to assess the possible risk of QT prolongation and TdP in humans. The main problem in cardiac safety pharmacology is how best to combine the capabilities of different methodologies with their strengths and limitations in order to detect the potential of one molecular entity to induce a lethal arrhythmia of very low clinical incidence. This publication will review the current methodologies, focusing on the alternative methods to animal experimentation, including an overview of cardiac modeling.

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Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart

Cited by 66 publications

References 80 publications

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

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

Preclinical cardio-safety assessment of torsadogenic risk and alternative methods to animal experimentation: The inseparable twins

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