Animal models are used in the discovery of new drugs and vaccines used to treat human diseases. In addition to helping test drug efficacy, studies in laboratory animals are also used to help determine what unwanted effects the drug may have. These safety studies enable developers to deselect candidate molecules with associated hazards and ensure only those with better safety profiles are progressed into human clinical trials. Unwanted side effects on the cardiovascular system are a very common cause of drug molecule deselection during the early phases of development. Clinical data suggests that if a drug causes even a slight increase in arterial blood pressure (e.g. 2mmHg), it can significantly increase the risk of heart attack or a stroke. Increases in resting heart rate are also known to be associated with an increased risk of sudden cardiac death and heart failure. Drugs can also sometimes cause a disturbance to the heart’s normal rhythm (drug-induced arrhythmia), which, unsurprisingly, can have serious consequences. To protect the safety of patients and volunteers undergoing clinical trials on new medicines, the effects of the new drug on arterial blood pressure, heart rate and ECG must first be assessed in a non-rodent species, usually using implantable telemetry devices. Previous datasets have shown good concordance of drug-induced changes in heart rate and blood pressure between large animals and humans (sensitivity 78% and specificity 79%). Telemetry in rodents tends to be used at an earlier stage in the development of new medicines to obtain an initial assessment of cardiovascular risk. Previously published data has examined the translation of drug-induced cardiovascular effects from the rat to larger animal species and also shown good agreement of results (sensitivity 84% and specificity 71%). The study also calculated the positive and negative predictive values of the rat telemetry assay (PPV and NPV). PPV is the probability of translation of a positive effect (i.e., a change in blood pressure or heart rate caused by the drug). NPV is the probability of translation of a negative effect (i.e. no drug-related effect). PPV and NPV values were 90% and 60%, respectively. This means that if a drug has an effect in the rat telemetry assay, there is a 90% probability that it will be seen in a larger animal species. This makes the rat telemetry assay a very useful tool for early identification of cardiovascular side-effects which might affect a drug’s future development. At Vivonics, we utilise this assay to help our clients make early go/no-go decisions on molecules or chemical series and to understand the inherent risk of drug targets.
Why is the rat telemetry assay a useful tool in safety pharmacology studies?
Bhatt et al., Preclinical to Clinical Translation of Hemodynamic Effects in Cardiovascular Safety Pharmacology Studies, TOXICOLOGICAL SCIENCES, 169(1), 2019, 272–279