Cardiac Safety Committee
Cardiac Safety Committee
The mission of the HESI Cardiac Safety Technical Committee is to: improve public health by reducing unanticipated cardiovascular-related adverse effects from drugs or chemicals; and develop innovative approaches to support early detection and prediction as well as improved understanding of cardiovascular toxicology and pathobiology.
HESI Cardiac Safety Committee Request for Proposals
The HESI Cardiac Safety Committee seeks research proposals for studies involving human-relevant, mechanism-based assays evaluating cardiac safety liabilities. In 2019, the HESI Cardiac Safety Committee was awarded a U01 grant from the U.S. FDA on the “Evaluation of Integrated Human-Relevant Approaches to Identify Drug-Induced Cardiovascular Liabilities.” This grant will support HESI in funding and managing novel, in vitro experimental studies to develop targeted mechanistic data to inform drug safety assessment for key cardiac “failure modes.” HESI Cardiac Safety Committee members identified six main failure modes, CV liabilities contributing to drug attrition, as follows:
1. Vasoactivity changes (blood pressure/heart rate)
2. Inotropy changes (contractility/ejection fraction)
3. Action potential changes (electrophysiology)
4. Cardiomyocyte/Myocardial injury (myocardial necrosis/hypertrophy)
5. Valvular injury/proliferation (regurgitant flow)
6. Endothelial injury/coagulation (hemorrhage, thrombosis)
HESI is seeking proposals for a 12-month sub-award under this grant for studies involving human-relevant, mechanism-based assays evaluating cardiac safety liabilities.
The Cardiac Safety Committee will convene a 2 day workshop to discuss mechanistic approaches to cardiovascular safety assessment.
This meeting was held 18-19 June 2015.
This update workshop brought together global regulators, academicians, drug developers and CRO scientists. The focus of the workshop was on providing information on the latest project developments with the goal for there to be a high level of participant interaction.
This workshop was co-sponsored by the HESI Cardiac Safety Technical Committee.
Automated patch clamp (APC) instruments enable efficient evaluation of electrophysiologic effects of drugs on human cardiac currents in heterologous expression systems. Differences in experimental protocols, instruments, and dissimilar site procedures affect the variability of IC50 values characterizing drug block potency. This impacts the utility of APC platforms for assessing a drug’s cardiac safety margin. We determined variability of APC data from multiple sites that measured blocking potency of 12 blinded drugs (with different levels of proarrhythmic risk) against four human cardiac currents (hERG [IKr], hCav1.2 [L-Type ICa], peak hNav1.5, [Peak INa], late hNav1.5 [Late INa]) with recommended protocols (to minimize variance) using five APC platforms across 17 sites.
Voltage-sensitive optical (VSO) sensors offer a minimally invasive method to study the time course of repolarization of the cardiac action potential (AP). This Comprehensive in vitro Proarrhythmia Assay (CiPA) cross-platform study investigates protocol design and measurement variability of VSO sensors for preclinical cardiac electrophysiology assays.
Contractility of the myocardium engines the pumping function of the heart and is enabled by the collective contractile activity of its muscle cells: cardiomyocytes. The effects of drugs on the contractility of human cardiomyocytes in vitro can provide mechanistic insight that can support the prediction of clinical cardiac drug effects early in drug development. Cardiomyocytes differentiated from human-induced pluripotent stem cells have high potential for overcoming the current limitations of contractility assays because they attach easily to extracellular materials and last long in culture, while having human- and patient-specific properties.
Drug-induced effects on cardiac contractility can be assessed through the measurement of the maximal rate of pressure increase in the left ventricle (LVdP/dtmax) in conscious animals, and such studies are often conducted at the late stage of preclinical drug development. Detection of such effects earlier in drug research using simpler, in vitro test systems would be a valuable addition to our strategies for identifying the best possible drug development candidates.
A consortium, multi-site approach to testing in vitro assay technology for prediction of drug-induced TdP. The authors sought to test calcium transient assays using the CiPA 28 drugs.