Development of a Complete Proarrhythmic Safety Profile for Drugs

DESCRIPTION (provided by applicant): ChanTest's goal is to commercialize a comprehensive non-clinical proarrhythmic profile that will screen compounds through a battery of models that span from the molecular (ion channels) to the multicellular (Purkinje fibers) to whole organ (Langendorff perfused heart) and finally the intact animal (open chest rabbit). This battery of assays will help identify arrhythmogenic drugs. Ideally, one would like a model that can directly identify a drug's ability to initiate TdP but the occurrence of TdP is very rare; making it unlikely that one would observe TdP in a typical human trial. Also, in order to initiate TdP in a torsadogenic model it is frequently necessary to greatly increase the sensitivity of the model, which may make false positives more likely. Since the occurrence of TdP for NARDs is unlikely, other markers or surrogates of TdP are used. Some examples are as follows. The hERG patch-clamping assay is a very sensitive assay, but it has falsely identified drugs as being torsadogenic. The strength of the Purkinje fiber model lies in its ability to identify compounds that have multiple ion channel effects. However, it is possible for false negatives to occur in this assay. For instance, the canine Purkinje fiber is insensitive to bepridil, a known torsadogenic drug. The isolated, Langendorff perfused rabbit heart model allows one to measure the effects of compounds on a wide range of parameters, including the QT interval and the monophasic action potential duration (MAPD) as well as other cardiac electrical parameters such as early afterdepolarizations (EADs), electrical instability, and alternans of the monophasic action potential duration (MAPD), which have been shown to be predictive of arrhythmogenic drugs. However, it should be stated that in vitro and ex vivo models are isolated. They are not influenced by autonomic or metabolic systems. Therefore, compounds also need to be tested in an intact animal model in order to have a complete proarrhythmic profile. The specific aim of this project is to develop an in vivo anesthetized rabbit model to complement the molecular cellular tissue and organ assays we already have in place, thereby providing the most complete proarrhythmic profile with both sensitivity and specificity to detect proarrhythmic drugs. We propose to infuse one group (A) of rabbits with methoxamine before and during dosage of the drugs. Another group (B) of rabbits will not be exposed to methoxamine. Instead the rabbit will only be sensitized using an alternans pacing stimulation procedure. We will test 5 torsadogenic (cisapride, quinidine, clofilium, dl-sotalol and DPI 201-106) and 2 non-torsadogenic compounds (verapamil and amiodarone). We will measure and compare changes in heart rate (HR), blood pressure (BP), the QT interval, MAPD, occurrence of EADs, incidence of arrhythmias and alternans of the MAPD50. Finally, we will compare the two groups of rabbits and the one with the most sensitive and specific responses will be our intact animal model.