Research laboratories engaged in the discovery of new drugs must be concerned with more than efficacy. Safety pharmacology testing is mandated by regulatory agencies in the USA and Europe. A recent addition to the tests requested by the United States Food and Drug Administration (FDA) is an assessment of the potential for any new drug, and all of its known metabolites, to induce delayed ventricular repolarization of the heart. This condition is more commonly known as """"""""QT interval prolongation"""""""" or QTIP. There are no tools to effectively screen potential drugs for their tendency to induce QTIP during the earliest stages of drug discovery. The available in vitro techniques have thus far provided poor correlation with human clinical trials. Animal models have been predictive of QTIP in humans, but studies in large animals (e.g. dogs and pigs) also require large quantities of drug. During early drug discovery, the entire supply of a new compound is measured as a few hundred milligrams and this is grossly insufficient to dose a dog. In this proposal, we describe a new screening method that we have developed for automatically collecting electrocardiograms (ECGs) from unrestrained rats. The virtue of this method is not limited to electrocardiography and for this reason, we have described the underlying invention as a """"""""catheter-electrode"""""""". The same technique simultaneously collects blood samples at intervals programmed by the researcher, with the intent of obtaining sufficient samples to produce a pharmacokinetic (PK) curve. When these blood samples are analyzed to quantitate the drug and its metabolites, the information can be correlated with the onset of QTIP, or other events seen in the corresponding electrocardiograms. Further, the same technique also permits programmed drug infusion, making it possible to determine whether QTIP (or another adverse indication in the ECG) is dose-dependent. This dose data is also requested by the FDA. The goal of the Phase 1 project is to transfer our new screening method for QTIP from the rat to a guinea pig model. The guinea pig is considered by the FDA to be a suitable small animal model for safety pharmacology testing of QTIP, based on similarities with human heart ion channels. A further goal is to determine whether representative drugs that are known (or, not known) to induce QTIP in humans will demonstrate the same effect (or lack of effect) in the guinea pig model.
