This thesis describes a series of experimental studies (in vitro, ex vivo, in vivo) conducted and integrated using modelling/scaling approaches to develop compartmental and physiologically based models from early cardiovascular screening and pharmacokinetic data to predict measured in vivo rabbit QTc PKPD data. A terminally anaesthetised rabbit model was set-up and evaluated to measure the in vivo PKPD QTc response with a set of marketed test compounds (cisapride, sparfloxacin, moxifloxacin) known to prolong the QT interval and a negative control (verapamil). Using pharmacodynamic data generated in the ex vivo rabbit ventricular wedge model, a concentration-response relationship for QT interval changes was determined. This was combined with rat pharmacokinetic parameters scaled using two single species allometry methods and cross-species protein binding data (rat, dog, rabbit, guinea-pig and human) in plasma, blood and heart tissue, investigated using the rapid equilibrium dialysis device, to develop a physiologically-based mechanistic model along with a semi-compartmental model to predict the rabbit response to the marketed tool compounds. A whole-body physiologically-based pharmacokinetic (PBPK) model suitably described the rat intravenous plasma concentration-time profile of each test compound and was translated to the rabbit using GastroPlus™ software. From the scaled approach, resultant simulated plasma and subsequent predicted heart concentration data successfully informed the PD model of the related QTc change. To demonstrate the functionality of the mechanistic model this was assessed against observed clearance and heart:plasma Kp ratio in the anaesthetised rabbit. The semi-PBPK compartmental model of the heart further supported the physiologically relevant heart compartment. This work is the first description of using PBPK modelling translation towards rabbit cardiovascular QT prolongation and demonstrates the potential for preclinical translation.
|Date of Award||2 Jun 2017|
- University Of Strathclyde
|Sponsors||University of Strathclyde|
|Supervisor||Edward Rowan (Supervisor) & Ruangelie Edrada-Ebel (Supervisor)|