Corrigendum: Optimization of an Cardiac Cell Model for Proarrhythmia Risk Assessment.

[This corrects the article on p. 616 in vol. 8, PMID: 28878692.

Uncertainty Quantification Reveals the Importance of Data Variability and Experimental Design Considerations for Proarrhythmia Risk Assessment.

The Comprehensive 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 model of the human ventricular action potential (AP) that integrates 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 assay.

Optimization of an Cardiac Cell Model for Proarrhythmia Risk Assessment.

Drug-induced Torsade-de-Pointes (TdP) has been responsible for the withdrawal of many drugs from the market and is therefore of major concern to global regulatory agencies and the pharmaceutical industry. The Comprehensive Proarrhythmia Assay (CiPA) was proposed to improve prediction of TdP risk, using models and multi-channel pharmacology data as integral parts of this initiative. Previously, we reported that combining dynamic interactions between drugs and the rapid delayed rectifier potassium current (IKr) with multi-channel pharmacology is important for TdP risk classification, and we modified the original O'Hara Rudy ventricular cell mathematical model to include a Markov model of IKr to represent dynamic drug-IKr interactions (IKr-dynamic ORd model).

Characterization of loperamide-mediated block of hERG channels at physiological temperature and its proarrhythmia propensity.

Background: Loperamide (Immodium®) is indicated for symptomatic control of diarrhea. It is a μ-opioid receptor agonist, and recently has been associated with misuse and abuse. At therapeutic doses loperamide has not been associated with cardiotoxicity.

Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-à-go-go-Related Gene) Channel-Drug Binding Kinetics and Multichannel Pharmacology.

Background: The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte. A set of drugs with known clinical torsade de pointes risk was selected to develop and calibrate the in silico model.

Characterization of the methemoglobin forming metabolites of benzocaine and lidocaine.

1. Topical anesthesia with benzocaine or lidocaine occasionally causes methemoglobinemia, an uncommon but potentially fatal disorder where the blood has a reduced ability to transport oxygen. Previous in vitro studies using human whole blood have shown that benzocaine causes more methemoglobin (MetHb) formation than lidocaine, and that both compounds require metabolic transformation to form the MetHb producing species.

The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative - Update on progress.

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.

A temperature-dependent in silico model of the human ether-à-go-go-related (hERG) gene channel.

Introduction: Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-à-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents.

A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm.

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.

Impact of Pathologists and Evaluation Methods on Performance Assessment of the Kidney Injury Biomarker, Kim-1.

Attempts to characterize and formally qualify biomarkers for regulatory purposes have raised questions about how histological and histopathological methods impact the evaluation of biomarker performance. A group of pathologists was asked to analyze digitized images prepared from rodent kidney injury experiments in studies designed to investigate sources of variability in histopathology evaluations. Study A maximized variability by using samples from diverse studies and providing minimal guidance, contextual information, or opportunities for pathologist interaction.

Modeling and simulation for medical product development and evaluation: highlights from the FDA-C-Path-ISOP 2013 workshop.

Medical-product development has become increasingly challenging and resource-intensive. In 2004, the Food and Drug Administration (FDA) described critical challenges facing medical-product development by establishing the critical path initiative [1]. Priorities identified included the need for improved modeling and simulation tools, further emphasized in FDA's 2011 Strategic Plan for Regulatory Science [Appendix].

A Critical Role for Immune System Response in Mediating Anti-influenza Drug Synergies Assessed by Mechanistic Modeling.

Influenza virus infections represent a serious public health problem worldwide, due to the rapid emergence of drug resistance. One strategy to improve treatment efficacy is to combine drugs that act synergistically. Potentially useful drug combinations are typically identified through empirical testing using in vitro and animal models, but the complexity of the clinical situation warrants the use of more careful analysis and sophisticated approaches.

More methemoglobin is produced by benzocaine treatment than lidocaine treatment in human in vitro systems.

The clinical use of local anesthetic products to anesthetize mucous membranes has been associated with methemoglobinemia (MetHba), a serious condition in which the blood has reduced capacity to carry oxygen. An evaluation of spontaneous adverse event reporting of MetHba submitted to FDA through 2013 identified 375 reports associated with benzocaine and 16 reports associated with lidocaine. The current study was performed to determine the relative ability of benzocaine and lidocaine to produce methemoglobin (MetHb) in vitro.

EADB: an estrogenic activity database for assessing potential endocrine activity.

Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the body's endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways.

Comparison of urinary and serum levels of di-22:6-bis(monoacylglycerol)phosphate as noninvasive biomarkers of phospholipidosis in rats.

Phospholipidosis (PLD), an abnormal accumulation of phospholipids within tissues, is observed during the preclinical testing of many pharmaceutical drugs. Diagnosis of PLD is currently based on morphologic criteria. An understanding of the clinical incidence of PLD and its possible relationship to adverse drug reactions has been hampered by the absence of noninvasive biomarkers for PLD.

Comparison of the diagnostic accuracy of di-22:6-bis(monoacylglycerol)phosphate and other urinary phospholipids for drug-induced phospholipidosis or tissue injury in the rat.

Cationic amphiphilic drugs and aminoglycoside antibiotics can induce phospholipidosis (PLD), an abnormal accumulation of phospholipids in lysosome-derived vesicles, in preclinical studies. The incidence of PLD in patients and its clinical relevance are difficult to assess without noninvasive biomarkers. Di-docosahexaenoyl bis(monoacylglycerol)phosphate (di-22:6-BMP) is a phospholipid that is enriched in lysosomal membranes and a proposed urinary biomarker of drug-induced PLD.

(Q)SAR modeling and safety assessment in regulatory review.

The ability to predict clinical safety based on chemical structures is becoming an increasingly important part of regulatory decision making. (Quantitative) structure-activity relationship ((Q)SAR) models are currently used to evaluate late-arising safety concerns and possible nonclinical effects of a drug and its related compounds when adequate safety data are absent or equivocal. Regulatory use will likely increase with the standardization of analytical approaches, more complete and reliable data collection methods, and a better understanding of toxicity mechanisms.

Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs.

The safe disposal of unused opioid drugs is an area of regulatory concern. While toilet flushing is recommended for some drugs to prevent accidental exposure, there is a need for data that can support a more consistent disposal policy based on an assessment of relative risk. For drugs acting at the Mu-opioid receptor (MOR), published measurements of binding affinity (K(i)) are incomplete and inconsistent due to differences in methodology and assay system, leading to a wide range of values for the same drug thus precluding a simple and meaningful relative ranking of drug potency.

Biomarkers of endothelial cell activation serve as potential surrogate markers for drug-induced vascular injury.

Drug-induced vascular injury (DIVI) is a nonclinical finding that often confounds the toxicological evaluation of investigational drugs, but there is an absence of qualified biomarkers that can be used to detect and monitor its appearance in animals and patients during drug development and clinical use. It is well known that endothelial cell (EC) activation plays a key role in the expression and evolution of DIVI, and the various immunological and inflammatory factors involved in its expression may serve as potential biomarker candidates. Activated ECs change their morphology and gene expression, generating endothelial adhesion molecules, pro-coagulant molecules, cytokines, chemokines, vasodilators, nitric oxide, and acute-phase reactants.

'Impedance matching' of data sets in biomarker research.

The goal of biomarker research in drug development is to identify better ways of monitoring the effects of drugs on biological systems. Biomarker data are used to support decision making at various stages in the drug development process, and are also used to provide information on how drug use might be optimized in different patient populations. The evaluation and qualification of new safety biomarkers includes a rigorous analysis of the ability of a given biomarker to report specific pathological events at the cellular, tissue or systemic level.

Reassessing the validity of surrogate markers of drug efficacy in the treatment of coronary artery disease.

Surrogate markers of disease progression and drug efficacy have become an essential part of cardiovascular drug development. Some surrogate markers, such as LDL-cholesterol (LDL-C), have been studied extensively and are widely accepted as valid indicators of cardiovascular risk and as a basis for regulatory approval. Other markers, such as carotid intima-media thickness (IMT), can provide insights into coronary atherosclerosis, but their utility as surrogate endpoints remains uncertain.

What happens when cardiac Na channel function is compromised? 2. Numerical studies of the vulnerable period in tissue altered by drugs.

Objective: The fate of an impulse arising from stimulation is determined by the ability of the wave front to recruit sufficient Na channels from adjacent cells. Previous numerical studies of mutant Na channels revealed both the velocity of a conditioning wave and the recruiting capacity of the front as determinants of the vulnerable period (VP), an interval within which excitation results in unidirectional conduction. Drugs that block excitatory Na channels in a voltage dependent manner, such as antiarrhythmics, abused substances and antidepressants, slow the restoration of Na conductance trailing an action potential and are associated with proarrhythmia and sudden cardiac death.

What happens when cardiac Na channels lose their function? 1--numerical studies of the vulnerable period in tissue expressing mutant channels.

Objective: The vulnerable period (VP) defines an interval during which premature impulses can trigger reentrant arrhythmias leading to ventricular fibrillation and sudden death. The mechanistic basis of the success or failure of impulse propagation during the VP remains unclear. Recent clinical reports of gene mutations, drugs and cardiac disease link a variety of often lethal conditions with loss of cardiac Na channel function (NaLOF) and reentrant proarrhythmia.