Modelling hemodynamics regulation in rats and dogs to facilitate drugs safety risk assessment.

Pharmaceutical companies routinely screen compounds for hemodynamics related safety risk. secondary pharmacology is initially used to prioritize compounds while studies are later used to quantify and translate risk to humans. This strategy has shown limitations but could be improved via the incorporation of molecular findings in the animal-based toxicological risk assessment.

Anticancer drugs and cardiotoxicity: the role of cardiomyocyte and non-cardiomyocyte cells.

Cardiotoxicity can be defined as "chemically induced heart disease", which can occur with many different drug classes treating a range of diseases. It is the primary cause of drug attrition during pre-clinical development and withdrawal from the market. Drug induced cardiovascular toxicity can result from both functional effects with alteration of the contractile and electrical regulation in the heart and structural changes with morphological changes to cardiomyocytes and other cardiac cells.

RYR2 deficient human model identifies calcium handling and metabolic dysfunction impacting pharmacological responses.

Creation of disease models utilizing hiPSCs in combination with CRISPR/Cas9 gene editing enable mechanistic insights into differential pharmacological responses. This allows translation of efficacy and safety findings from a healthy to a diseased state and provides a means to predict clinical outcome sooner during drug discovery. Calcium handling disturbances including reduced expression levels of the type 2 ryanodine receptor (RYR2) are linked to cardiac dysfunction; here we have created a RYR2 deficient human cardiomyocyte model that mimics some aspects of heart failure.

Computational approaches identify a transcriptomic fingerprint of drug-induced structural cardiotoxicity.

Structural cardiotoxicity (SCT) presents a high-impact risk that is poorly tolerated in drug discovery unless significant benefit is anticipated. Therefore, we aimed to improve the mechanistic understanding of SCT. First, we combined machine learning methods with a modified calcium transient assay in human-induced pluripotent stem cell-derived cardiomyocytes to identify nine parameters that could predict SCT.

Application of microphysiological systems for nonclinical evaluation of cell therapies.

Microphysiological systems (MPS) are gaining broader application in the pharmaceutical industry but have primarily been leveraged in early discovery toxicology and pharmacology studies with small molecules. The adoption of MPS offers a promising avenue to reduce animal use, improve in-vitro-to-in-vivo translation of pharmacokinetics/pharmacodynamics and toxicity correlation, and provide mechanistic understanding of model species suitability. While MPS have demonstrated utility in these areas with small molecules and biologics, MPS models in cell therapy development have not been fully explored, let alone validated.

Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes.

Advances in hiPSC isolation and reprogramming and hPSC-CM differentiation have prompted their therapeutic application and utilization for evaluating potential cardiovascular safety liabilities. In this perspective, we showcase key efforts toward the large-scale production of hiPSC-CMs, implementation of hiPSC-CMs in industry settings, and recent clinical applications of this technology. The key observations are a need for traceable gender and ethnically diverse hiPSC lines, approaches to reduce cost of scale-up, accessible clinical trial datasets, and transparent guidelines surrounding the safety and efficacy of hiPSC-based therapies.

Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics.

Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated.

Prediction of inotropic effect based on calcium transients in human iPSC-derived cardiomyocytes and machine learning.

Functional changes to cardiomyocytes are undesirable during drug discovery and identifying the inotropic effects of compounds is hence necessary to decrease the risk of cardiovascular adverse effects in the clinic. Recently, approaches leveraging calcium transients in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been developed to detect contractility changes, induced by a variety of mechanisms early during drug discovery projects. Although these approaches have been able to provide some predictive ability, we hypothesised that using additional waveform parameters could offer improved insights, as well as predictivity.

approaches in organ toxicity hazard assessment: Current status and future needs for predicting heart, kidney and lung toxicities.

The kidneys, heart and lungs are vital organ systems evaluated as part of acute or chronic toxicity assessments. New methodologies are being developed to predict these adverse effects based on and approaches. This paper reviews the current state of the art in predicting these organ toxicities.

Deriving waveform parameters from calcium transients in human iPSC-derived cardiomyocytes to predict cardiac activity with machine learning.

Human induced pluripotent stem cell-derived cardiomyocytes have been established to detect dynamic calcium transients by fast kinetic fluorescence assays that provide insights into specific aspects of clinical cardiac activity. However, the precise derivation and use of waveform parameters to predict cardiac activity merit deeper investigation. In this study, we derived, evaluated, and applied 38 waveform parameters in a novel Python framework, including (among others) peak frequency, peak amplitude, peak widths, and a novel parameter, shoulder-tail ratio.

An Extensive Metabolomics Workflow to Discover Cardiotoxin-Induced Molecular Perturbations in Microtissues.

Discovering modes of action and predictive biomarkers of drug-induced structural cardiotoxicity offers the potential to improve cardiac safety assessment of lead compounds and enhance preclinical to clinical translation during drug development. Cardiac microtissues are a promising, physiologically relevant, in vitro model, each composed of ca. 500 cells.

Intra- and intercellular signaling pathways associated with drug-induced cardiac pathophysiology.

Cardiac physiology and homeostasis are maintained by the interaction of multiple cell types, via both intra- and intercellular signaling pathways. Perturbations in these signaling pathways induced by oncology therapies can reduce cardiac function, ultimately leading to heart failure. As cancer survival increases, related cardiovascular complications are becoming increasingly prevalent, thus identifying the perturbations and cell signaling drivers of cardiotoxicity is increasingly important.

Cardiovascular microphysiological systems (CVMPS) for safety studies - a pharma perspective.

The integrative responses of the cardiovascular (CV) system are essential for maintaining blood flow to provide oxygenation, nutrients, and waste removal for the entire body. Progress has been made in independently developing simple in vitro models of two primary components of the CV system, namely the heart (using induced pluripotent stem-cell derived cardiomyocytes) and the vasculature (using endothelial cells and smooth muscle cells). These two in vitro biomimics are often described as immature and simplistic, and typically lack the structural complexity of native tissues.

Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective.

Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation.

Current and future approaches to nonclinical cardiovascular safety assessment.

Our goal is to accurately predict all types of cardiovascular events in patients utilising nonclinical cardiovascular safety data. In the past two decades, cardiovascular safety science has primarily focused on events associated with the electrocardiogram. Broadening out to other cardiovascular parameters, we share real-life case studies that highlight our progress towards improved and better-informed project progression based upon use of disease models, mechanism-based translation and structure-function relationships.

Drug-induced myocardial dysfunction - recommendations for assessment in clinical and pre-clinical studies.

: Drug-induced myocardial dysfunction is an important safety concern during drug development. Oncology compounds can cause myocardial dysfunction, leading to decreased left ventricular ejection fraction and heart failure via several mechanisms. Cardiovascular imaging has a major role in the early detection and monitoring of cardiotoxicity.

A pharmacological characterization of electrocardiogram PR and QRS intervals in conscious telemetered rats.

Introduction: The conscious telemetered rat is widely used as an early in vivo screening model for assessing the cardiovascular safety of novel pharmacological agents. The current study aimed to identify its utility in assessing electrocardiogram (ECG) PR and QRS interval changes.

Method: Male Han-Wistar rats (~250 g) were implanted with radio-telemetry devices for the recording of ECG and haemodynamic parameters.

On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships.

Functional human-on-a-chip systems hold great promise to enable quantitative translation to in vivo outcomes. Here, we explored this concept using a pumpless heart only and heart:liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PKPD) relationship for terfenadine. There was a time dependent drug-induced increase in field potential duration in the cardiac compartment in response to terfenadine and that response was modulated using a metabolically competent liver module that converted terfenadine to fexofenadine.

Exosomal delivery of doxorubicin enables rapid cell entry and enhanced in vitro potency.

Doxorubicin is a chemotherapeutic agent that is commonly used to treat a broad range of cancers. However, significant cardiotoxicity, associated with prolonged exposure to doxorubicin, limits its continued therapeutic use. One strategy to prevent the uptake of doxorubicin into cardiac cells is the encapsulation of the drug to prevent non-specific uptake and also to improve the drugs' pharmacokinetic properties.

Information-Derived Mechanistic Hypotheses for Structural Cardiotoxicity.

Adverse events resulting from drug therapy can be a cause of drug withdrawal, reduced and or restricted clinical use, as well as a major economic burden for society. To increase the safety of new drugs, there is a need to better understand the mechanisms causing the adverse events. One way to derive new mechanistic hypotheses is by linking data on drug adverse events with the drugs' biological targets.

Characterization and Validation of a Human 3D Cardiac Microtissue for the Assessment of Changes in Cardiac Pathology.

Pharmaceutical agents despite their efficacy to treat disease can cause additional unwanted cardiovascular side effects. Cardiotoxicity is characterized by changes in either the function and/or structure of the myocardium. Over recent years, functional cardiotoxicity has received much attention, however morphological damage to the myocardium and/or loss of viability still requires improved detection and mechanistic insights.

Cytochrome P450 2J2: Potential Role in Drug Metabolism and Cardiotoxicity.

Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2). The biologic effects of EETs, including their protective effects on inflammation and vasodilation, are diverse because, in part, of their ability to act on a variety of cell types. In addition, CYP2J2 metabolizes both exogenous and endogenous substrates and is involved in phase 1 metabolism of a variety of structurally diverse compounds, including some antihistamines, anticancer agents, and immunosuppressants.

Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery.

Enhancing the early detection of new therapies that are likely to carry a safety liability in the context of the intended patient population would provide a major advance in drug discovery. Microphysiological systems (MPS) technology offers an opportunity to support enhanced preclinical to clinical translation through the generation of higher-quality preclinical physiological data. In this review, we highlight this technological opportunity by focusing on key target organs associated with drug safety and metabolism.

From the Cover: High-Throughput Imaging of Cardiac Microtissues for the Assessment of Cardiac Contraction during Drug Discovery.

Cardiotoxicity is a common cause of attrition in preclinical and clinical drug development. Current in vitro approaches have two main limitations, they either are limited to low throughput methods not amendable to drug discovery or lack the physiological responses to allow an integrated risk assessment. A human 3D cardiac microtissue containing human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), cardiac endothelial cells and cardiac fibroblast were used to assess their suitability to detect drug induced changes in cardiomyocyte contraction.