AIMS: Current pharmacokinetic-pharmacodynamic models describing the haemodynamic changes often do not include necessary feedback mechanisms. These models provide adequate description of current data but may fail to adequately extrapolate to additional scenarios. This study aims to develop a minimal model to describe the short-term changes of haemodynamics that can be used as the basis for model development by future researchers. METHODS: A minimal haemodynamic model was developed to describe the influence of drugs on blood pressure components. The model structure was defined based on known mechanisms and previously published models. The model was evaluated under 2 different simulation settings. The model parameters were calibrated to describe (without estimation) the haemodynamics of 2 antihypertensive drugs with data extracted from the literature. Structural identifiability analysis was done using various combinations of the observed variable. RESULTS: The proposed model structure includes mean arterial pressure, heart rate and stroke volume and is composed of 4 states described by differential equations. Model evaluation showed flexibility in describing the haemodynamics at different target perturbations. Overlay plots of model predictions and literature data showed a good description without data fitting. The structural identifiability analysis revealed all model parameters and initial conditions were identifiable only when heart rate, mean arterial pressure and cardiac output were measured together. CONCLUSIONS: A minimal model of the haemodynamic system was developed and evaluated. The model accounted for short-term haemodynamic feedback processes. We propose that this model can be used as the basis for future pharmacometric analyses of drugs acting on the haemodynamic system.
AIMS: Current pharmacokinetic-pharmacodynamic models describing the haemodynamic changes often do not include necessary feedback mechanisms. These models provide adequate description of current data but may fail to adequately extrapolate to additional scenarios. This study aims to develop a minimal model to describe the short-term changes of haemodynamics that can be used as the basis for model development by future researchers. METHODS: A minimal haemodynamic model was developed to describe the influence of drugs on blood pressure components. The model structure was defined based on known mechanisms and previously published models. The model was evaluated under 2 different simulation settings. The model parameters were calibrated to describe (without estimation) the haemodynamics of 2 antihypertensive drugs with data extracted from the literature. Structural identifiability analysis was done using various combinations of the observed variable. RESULTS: The proposed model structure includes mean arterial pressure, heart rate and stroke volume and is composed of 4 states described by differential equations. Model evaluation showed flexibility in describing the haemodynamics at different target perturbations. Overlay plots of model predictions and literature data showed a good description without data fitting. The structural identifiability analysis revealed all model parameters and initial conditions were identifiable only when heart rate, mean arterial pressure and cardiac output were measured together. CONCLUSIONS: A minimal model of the haemodynamic system was developed and evaluated. The model accounted for short-term haemodynamic feedback processes. We propose that this model can be used as the basis for future pharmacometric analyses of drugs acting on the haemodynamic system.
Authors: Yu Fu; Hadi Taghvafard; Medhat M Said; Eric I Rossman; Teresa A Collins; Stéphanie Billiald-Desquand; Derek Leishman; Piet H van der Graaf; J G Coen van Hasselt; Nelleke Snelder Journal: CPT Pharmacometrics Syst Pharmacol Date: 2022-03-18