TAILSPIN - Translation of inotropic and lusitropic drug effects from rats to humans based on comprehensive in silico models.

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Background: The late detection of adverse cardiovascular drug effects is a major concern in drug development which can only be tackled by increasing the prediction accuracy of preclinical safety pharmacology studies. Drug regulatory bodies require the evaluation of drug effects on blood pressure and several electrophysiological endpoints. However, recent research has suggested that the evaluation of drug effects on the heart´s contractility and relaxation, referred to as inotropic and lusitropic drug effects, is just as important since both increasing/ decreasing contractility and impaired relaxation can be harmful to patients. Their evaluation is commonly based on endpoints in left ventricular pressure (LVP) recordings and the conscious telemetered rat is a popular animal model because excitation, contraction, and relaxation in rat and human hearts share many similarities. However, morphological and functional differences exist that hamper the translation of inotropic and lusitropic drug effects from rats to humans. Objectives and Methodology: The overall objective of the proposed project is to develop a computational approach that improves the translation of inotropic and lusitropic drug effects from rats to humans. This will be achieved by addressing four specific objectives. Firstly, I will build, calibrate, and validate in silico models (simulators) that simulate rat and human ventricular electromechanics and haemodynamics before and after drug administration. Secondly, I will train and validate Gaussian process regression models (emulators) that rapidly emulate LVP biomarker data provided by the rat and human simulators. Thirdly, I will perform global sensitivity analyses on emulated data to quantify the impact of potential drug targets on the LVP biomarkers in both rats and humans. Fourthly, I will create and validate a translation strategy that identifies inversely, based on the rat emulator and experimental rat LVP biomarker data, how the drug acts in the cardiovascular system and then uses these information as input for the human emulator to predict LVP biomarker drug effects in humans.Significance: The successful completion of the proposed project will not only shed light on the strengths and limitations of the conscious telemetered rat model for the evaluation of inotropic and lusitropic drug effects in humans but will also overcome the existing limitations by an innovative computational approach. This will help to detect adverse inotropic and lusitropic effects already in the preclinical phase of drug development.