Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation

International audienceIntroduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer proarrhythmic liability to drug candidates intended for human use.Topics covered: Key talks delivered at the ‘CiPA on my mind’ session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e.g., biological materials (ion channels and pluripotent stem cell-derived cardiomyocytes), study platforms, drug solutions, and data analysis] of CiPA core assays are critically examined.Discussion: In order to advance the CiPA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by CiPA stakeholders is necessary to expedite solutions to pending and newly arising issues. Once a study protocol is proved to yield robust and reproducible results within and across laboratories, it can be implemented as qualified regulatory procedure

799-2 Left Ventricular (LV) and Myocyte Electrophysiology with the Development of Dilated Cardiomyopathy (DCM); Effects of Angiotensin II Receptor (AT1 AT-II) Blockade

Ventricular arrhythmias are a significant cause of morbidity and mortality with DCM, and AT1 AT-II receptor activation has been implicated to play a role in arrhythmogenesis. However, the effects of AT1, AT-II receptor activation on changes in LV function and myocyte electrophysiology during the progression of DCM remain unexplored. Accordingly, this study measured weekly changes in LV function (ejection fraction, LVEF; peak systolic wall stress, LVWS) and surface electrocardiography (R-R interval, QRS duration, QTc interval), and myocyte action potentials (resting membrane, RM; upstroke velocity, Vmax; duration at 90% repolarization, APD90) at terminal study in 3 groups of dogs (n=6/group): DCM, chronic pace (216 bpm, 4 weeks); DCM/AT-BLOCK, chronic pace and treatment with a specific non-peptide AT1 AT-II antagonist (SR 47436 (BMS 186295); 30mg/kg BID); and control (CON). All measurements were made with the pacemaker deactivated.LVEF (%)LVWS (g/cm2)R-R (ms).QRS (ms).QTc (ms)Week 2:CON68.7±3.2133±14646±9958.4±1.3291±13DCM40.9±4.1*184±16*519±4060.7±1.9316±9DCM/AT-Block44.1±3.7*138±10+540±566.32±1.2*325±9Week4:CON73.1±2.4127±10629±4557.6±1.4314±9DCM35.2±3.5*223±16*505±41*62.0±1.9313±9DCM/AT-Block35.2±2.7*160±13*+578±4865.7±1.5*296±6*p<0.05 vs CON+p<0.05 vs DCMWith DCM, RM (-71±l* vs -78±1mV) and APD90 (257±9* vs 226±7ms) increased, and Vmax decreased (121±5* vs 158±9V/s) compared to CON. In contrast, with AT-BLOCK, RM became more negative (-76±1+mV), APD90 was reduced (183±14*+) and Vmax increased (165±13+).SummaryAT1 AT-II receptor blockade during the progression of DCM caused significant changes in LV myocardial conduction and myocyte action potentials. These results suggest that AT1 AT-II receptor activation plays a contributory role toward the changes in LV electrophysiology with DCM

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