Drug safety Africa: An overview of safety pharmacology & toxicology in South Africa.

This meeting report is based on presentations given at the first Drug Safety Africa Meeting in Potchefstroom, South Africa from November 20-22, 2018 at the North-West University campus. There were 134 attendees (including 26 speakers and 34 students) from the pharmaceutical industry, academia, regulatory agencies as well as 6 exhibitors. These meeting proceedings are designed to inform the content that was presented in terms of Safety Pharmacology (SP) and Toxicology methods and models that are used by the pharmaceutical industry to characterize the safety profile of novel small chemical or biological molecules. The first part of this report includes an overview of the core battery studies defined by cardiovascular, central nervous system (CNS) and respiratory studies. Approaches to evaluating drug effects on the renal and gastrointestinal systems and murine phenotyping were also discussed. Subsequently, toxicological approaches were presented including standard strategies and options for early identification and characterization of risks associated with a novel therapeutic, the types of toxicology studies conducted and relevance to risk assessment supporting first-in-human (FIH) clinical trials and target organ toxicity. Biopharmaceutical development and principles of immunotoxicology were discussed as well as emerging technologies. An additional poster session was held that included 18 posters on advanced studies and topics by South African researchers, postgraduate students and postdoctoral fellows

General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration–sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model‐based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm

Association of Helicobacter with cholangiohepatitis in cats

Infection with Helicobacter spp. is increasingly linked with hepatobiliary inflammation and neoplasia in people and in a variety of animals. We sought to determine if Helicobacter species infection is associated with cholangiohepatitis in cats. Deoxyribonucleic acid was extracted from tissue blocks from cats with cholangiohepatitis (32), noninflammatory liver disease (13), and cats with normal liver histology (4). Deoxyribonucleic acid was polymerase chain reaction-amplified with 2 sets of Helicobacter genus-specific primers, gel purified, and sequenced. Polymerase chain reaction-positive hepatic tissue was further examined with Steiner's stain, immunocytochemistry for Helicobacter species, and eubacterial fluorescent in situ hybridization. Gastric tissues of cats with known Helicobacter infection status served as controls for deoxyribonucleic acid extraction and sequence comparison. Helicobacter species were detected in 2/32 cats with cholangiohepatitis, and 1/17 controls. Sequences had 100% identity with Helicobacter species liver, Helicobacter pylori, and Helicobacter fenelliae/cinaedii in a cat with suppurative cholangitis, Helicobacter species liver, Helicobacter pylori, and Helicobacter nemistrineae in a cat with mild lymphocytic portal hepatitis, and Helicobacter bilis in a cat with portosystemic vascular anomaly. In contrast, sequences from gastric biopsies showed highest homology (99-100%) to "Helicobacter heilmannii," Helicobacter bizzozeronii, Helicobacter felis, and Helicobacter salomonis. Fluorescent in situ hybridization revealed a semicurved bacterium, with Helicobacter-like morphology, in an intrahepatic bile duct of the cat with suppurative cholangitis. This study has identified Helicobacter deoxyribonucleic acid in 2/32 cats with cholangiohepatitis and 1/13 cats with noninflammatory liver disease. Deoxyribonucleic acid sequences of hepatic Helicobacter species were distinct from those found in the stomach and are broadly consistent with those identified in cat intestine and bile, and hepatobiliary disease in people and rodents. Copyrigh

Human ex-vivo action potential model for pro-arrhythmia risk assessment

While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of potentially important, high quality drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to record APs. Effects of torsadogenic (Dofetilide, D,L-Sotalol, Quinidine) and non-torsadogenic (Paracetamol, Verapamil) drugs were assessed on AP parameters (AP duration at 30% (APD30), 50% (APD50) and 90% (APD90) of repolarization, short-term variability (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations (EADs) at 1 and 2 Hz) to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 ascending concentrations in triplicate trabeculae from 5 hearts, with one time-matched control per heart. Electrophysiological stability of the model was not affected by 3 sequential applications of vehicle (0.1% dimethyl sulfoxide). Dofetilide, D,L-Sotalol and Quinidne exhibited a concentration-dependent increase in the manifestation of pro-arrhythmia markers. Paracetamol and Verapamil did not significantly alter anyone of the parameters used in this study and were classified as devoid of pro-arrhythmic risk. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to detect drug-induced AP effects. In conclusion, the human ex-vivo AP-based model provides an integrative translational assay assisting in decision/guidance for clinical development plans that could be used in conjunction with the new CiPA-proposed approach

An overview of the safety pharmacology society strategic plan

Safety Pharmacology studies are conducted to characterize the confidence by which biologically active new chemical entities (NCE) may be anticipated as safe. Non-clinical safety pharmacology studies aim to detect and characterize potentially undesirable pharmacodynamic activities using an array of in silico, in vitro and in vivo animal models. While a broad spectrum of methodological innovation and advancement of the science occurs within the Safety Pharmacology Society, the society also focuses on partnerships with health authorities and technology providers and facilitates interaction with organizations of common interest such as pharmacology, physiology, neuroscience, cardiology and toxicology. Education remains a primary emphasis for the society through content derived from regional and annual meetings, webinars and publication of its works it seeks to inform the general scientific and regulatory community. In considering the future of safety pharmacology the society has developed a strategy to successfully navigate forward and not be mired in stagnation of the discipline. Strategy can be defined in numerous ways but generally involves establishing and setting goals, determining what actions are needed to achieve those goals, and mobilizing resources within the society to accomplish the actions. The discipline remains in rapid evolution and its coverage is certain to expand to provide better guidance for more systems in the next few years. This overview from the Safety Pharmacology Society will outline the strategic plan from 2016 to 2018 and beyond and provide insight into the future of the discipline which builds upon a previous strategic plan established in 2009

General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration\u2013sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm

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

The appropriate and efficient assessment of drug-induced clinical QTc prolongation (a surrogate marker of Torsades de Pointes arrhythmia) remains a concern of drug developers and regulators worldwide. Refined and validated over 15+ years, the nonclinical ICH S7B guidance describes two core assays (in vitro hERG/IKr current & in vivo QT studies) to assess the potential for delayed ventricular repolarization. Incorporating these assays early in candidate selection has lead to: i) a low prevalence of QTc prolonging drugs in clinical trials, and ii) no drugs have been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical findings still minimally influence ICH E14-based strategies for interpreting clinical QTc prolongation, and defining proarrhythmic risk. In particular, the value of ICH S7B-based findings for candidates demonstrating minimal hERG/IKr block and minimal in vivo QTc prolongation at comparable clinical exposures (i.e., “double-negative nonclinical findings” are underestimated. Such reassuring nonclinical data has clear value assessing the risk of clinical QTc prolongation when clinical evaluation may be challenged by heart rate changes, exposure limitations, or safety considerations. The time has come to meaningfully merge nonclinical and clinical approaches to provide a more comprehensive and integrated proarrhythmia risk assessment strategy that complements advances described in ICH E14 amendments to enable more flexible clinical QTc risk assessments. Adoption of a truly integrative nonclinical/clinical risk assessment in the context of the low prevalence of QTc prolonging drugs would positively impact regulatory science, relieve the burden of extensive QTc monitoring, and streamline drug development