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

Selective heparanase localization in malignant melanoma

Heparanase (HPSE-1) is an endo-beta-D-glucuronidase that cleaves heparan sulfate proteoglycans (HSPG), and its expression has been associated with increased growth, metastasis, and angiogenesis of tumors. Since metastatic melanoma cells express high levels of HSPG and because melanoma tumors grow highly vascularized, we analyzed melanoma tissue specimens for HPSE-1 expression from experimental animals as well as from patients. Laser capture microdissection microscopy was used to extract melanoma cell populations and to isolate them from adjacent tissue. In experimental animals, a 29-fold upregulation of HPSE-1 expression was detected by real-time PCR in metastatic melanoma compared to normal lung tissue. Additionally, immunohistochemistry (IHC) revealed selective HPSE-1 staining in human metastatic melanoma when compared to primary melanoma tumors from the same patient. IHC also showed a marked staining for the enzyme around blood vessels and in vascularized regions. Our results provide evidence demonstrating that HPSE-1 likely plays important roles in regulating the in vivo growth and progression of melanoma. These results further emphasize the importance that therapies designed to block HPSE-1 activity may aid in controlling this type of cancer

Preclinical QT safety assessment: Cross-species comparisons and human translation from an industry consortium

AbstractIntroductionIn vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic.MethodsSix pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3–100mg/kg, p.o.) with telemetered ECGs (≥500Hz) obtained for 20–24h post-dose. Individual probabilistic QT–RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc–RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/μM) were derived for 1h centered on the moxifloxacin Tmax.ResultsAll QT–RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man.DiscussionThe current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the implementation of standardized QTc data presentation, QTc reference cycle lengths, and rate-correction coefficients can markedly improve the concordance of preclinical and clinical outcomes in most preclinical species

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

The Safety Pharmacology Society salary survey

Introduction Safety pharmacology is a growing discipline with scientists broadly distributed across international geographical regions. This electronic salary survey is the first to be distributed amongst the entire Safety Pharmacology Society (SPS) membership. An electronic survey was sent to all members of the Society. Categorical survey questions assessed membership employment types, annual incomes, and professional certifications, along with other associated career attributes. Methods This survey was distributed to the SPS membership that is comprised of safety pharmacologists, toxicologists and pharmacologists working globally in the pharmaceutical industry, at contract research organizations (CRO), regulatory agencies, and academia or within the technology provider industry. The survey was open for responses from December 2015 to March 2016. Results The survey response rate was 28% (129/453). North America (68%) was the region with the largest number of respondents followed by Europe (28%). A preponderance of respondents (77%) had 12 years of industry experience or more. 52% of responders earned annually between $40,000 and$120,000. As expected, salary was generally positively correlated with the number of years of experience in the industry or the educational background but there was no correlation between salary and the number of employee's directly supervised. The median salary was higher for male vs female respondents, but so was median age, indicative of no gender ‘salary gap’. Discussion Our 2016 SPS salary survey results showcased significant diversity regarding factors that can influence salary compensation within this discipline. These data provided insights into the complex global job market trends. They also revealed the level of scientific specialization embedded within the organization, presently uniquely positioned to support the dynamic career paths of current and future safety pharmacologists

Renal studies in safety pharmacology and toxicology: A survey conducted in the top 15 pharmaceutical companies

Introduction: What strategies are used to investigate renal toxicity in both ICH S7A compliant safety pharmacology studies and within repeat dose toxicity studies by large pharmaceutical companies today? Do single dose renal safety pharmacology studies have impact or utility in drug development or are we better placed to assess renal effects after multiple doses of compounds? How much mechanistic work is performed? What has the impact of the validation of the DIKI biomarkers been in terms on what companies are now measuring? What is the impact of renal/urinary safety study data upon progression of projects? Methods: A short anonymous survey was conducted, by invitation, to safety pharmacology representatives of the top 15 pharmaceutical companies, as defined by 2012 R&D portfolio size. A series of multiple choice questions were designed to explore the strategies used to investigate renal effects in both ICH S7A compliant safety pharmacology studies and within toxicology studies. Results: A 67% response rate was obtained. Nine out of ten companies conduct renal excretory measurements in toxicology studies whereas only five out of ten conduct renal safety pharmacology studies; and all of those 5 also conduct the renal excretory measurements in toxicology studies. A variety of parameters are measured and/or calculated as part of these studies, on a case by case basis, including regulatory qualified and non-qualified DIKI biomarkers. Finally, only one company has used renal/urinary functional data alone to stop a project, whereas the majority of respondents combine renal data with other target organ assessments to form a larger decision-making set. Conclusion: This short survey has highlighted areas of similarity, e.g. urinary measurements are more commonly taken on repeat dose toxicity studies and renal safety pharmacology studies have little utility and also differences such as the differing use of DIKI biomarkers in urinary safety studies, in the way large pharmaceutical companies assessed renal function

The incidence of spontaneous arrhythmias in telemetered beagle dogs, Göttingen Minipigs and Cynomolgus non-human primates: A HESI consortium retrospective analysis.

Characterization of the incidence of spontaneous arrhythmias to identify possible drug-related effects is often an important part of the analysis in safety pharmacology studies using telemetry.A retrospective analysis in non-clinical species with and without telemetry transmitters was conducted. Electrocardiograms (24 h) from male and female beagle dogs (n = 131), Göttingen minipigs (n = 108) and cynomolgus non-human primates (NHP; n = 78) were analyzed.Ventricular tachycardia (VT) was observed in 3% of the dogs but was absent in minipigs and NHPs. Ventricular fibrillation (VF) was not observed in the 3 species. Ventricular premature beats (VPBs) were more frequent during daytime and atrioventricular blocks (AVBs) were more frequent at night in all species. A limited number of animals exhibited a high arrhythmia frequency and there was no correlation between animals with higher frequency of an arrhythmia type and the frequency of other arrythmias in the same animals. Clinical chemistry or hematology parameters were not different with or without telemetry devices. NHP with a transmural left ventricular pressure (LVP) catheter exhibited a greater incidence of VPBs and PJCs compared to telemetry animals without LVP.All species were similar with regards to the frequency of ventricular ectopic beats (26-46%) while the dog seemed to have more frequent junctional complexes and AVB compared to NHP and minipigs. Arrhythmia screening may be considered during pre-study evaluations, to exclude animals with abnormally high arrhythmia incidence