Host: The Japanese Society of Toxicology
Drug-induced cardiotoxicity is still a major concern endangering patient health during clinical trials for new chemical entities. Accurate and effective assessment leading to selection of promising candidates without cardiotoxic potential is one of the most important strategies at the preclinical phase of drug development. In safety pharmacology testing, cardiovascular safety profiling is carried out using non-rodent species. In recent years, preclinical in vitro, in vivo, or in silico cardiac electrophysiological safety assessments, typified by predicting drug-induced long QT syndrome, have been enhanced. An additional consideration to drug effects on heart involves cardiac contractility. However, other cardiovascular adverse effects including congestive heart failure are often difficult to detect during the preclinical stage, and the methods for assessment of the effects of the candidates on cardiac function, like their cardiac inotropic and lusitropic potential, still have room for development. The evaluation for cardiac contractility still depends on load-dependent indexes. The LVdP/dtmax is suitable only when loading conditions are unchanged. The QA interval is affected by following factors: electro-pressor latency (e.g. the time from the opening sodium channels to binding of heavy meromyosin head to actin), contraction time during isovolumic systole, pulse wave propagation (distance from LV to transducer, or stiffness of the arterial tree). Many factors other than cardiac contractility are involved, and interpretation being examined only by these parameters remains elusive. The establishment of inotropic/lusitropic properties remains elusive under clinical/screening paradigms because of load-dependency of indices of contractility/lusitropy (e.g., dP/dtmax), and the end-systolic pressure-volume (PV) relationship is known as a gold standard for evaluating the inotropic potential. Recent improvement of PV catheter technology has made possible the accurate measurement of the left ventricular PV by the admittance method. This method incorporates elements of the conductance of blood flow and cardiac muscle combined with the capacitance of the myocardium. The measurement of PV using this method has been conducted mainly in rodents, but not in non-rodents. Preclinical studies in monkeys still occupy an important position in the toxicological field. In addition, the evaluation of cardiovascular safety profile for promising drugs is carried out using monkeys as one of the non-rodent species in safety pharmacology testing. Therefore, there is a need to increase the knowledge and awareness of available and reliable non-rodent models by adopting the PV loop method in order to identify the potential cardiac functional toxicity of new chemical entities. In addition to update cardiac electrophysiological assessments in nonclinical studies, I would like to present new approaches to hemodynamic assessment such as cardiac contractility.
