Michael Block (1), Rolf Burghaus (2), Karina Claassen (1), Thomas Eissing (1), Jörg Lippert (2), Stefan Willmann (1), Katrin Coboeken (1)
(1) Bayer Technology Services GmbH, Technology Development, Enabling Technologies, Computational Systems Biology, Leverkusen, Germany; (2) Bayer Pharma AG, Clinical Pharmacometrics, Wuppertal, Germany
Objectives: A physiologically-based (PB) cardiovascular (CV) model including a representation of heart (left, right atrium and ventricle), pulmonary, organ and venous/arterial hemodynamics was developed. The model is aimed to represent all relevant pressures and blood flows of the CV system at a physiological level under different healthy and pathophysiological conditions. Further the model aims for application in a full coupled PBPK/PD context including submodels for different drug-specific MoA’s like the Renin-Angiotensin-Aldosterone system.
Methods: The PB CV model was developed by use of the systems biology platform for PBPK and PD modeling including PK-Sim and MoBi. All relevant parameters (such as resistances, compliances, inertances, volumina..) were included based on available literature information [1-4]. The model was applied to different physiological states to investigate in detail the processes and mechanisms leading to changes in blood pressure, blood flows and related physiological conditions of the cardiovascular system. The model is designed in a manner ready to address short term hemodynamics at a scale of single heart beats and detailed changes of heart dynamics and the long-term changes on a timescale of weeks and months by a switch between a detailed model and a mean one acting on a larger timescale. Processes included in the model are the feedback mechanisms of the sympathetic and parasympathetic response on reduced oxygen consumption and changes by workload. For the analysis of pathophysiological disease states the corresponding conditions to address different types of hypertension (pulmonary/arterial) are included.
Results: The developed cardiovascular model is able to represent all relevant properties including the dynamic changes of related blood pressures including systemic arterial diastolic and systolic blood pressure and pulmonary pressures, as well as blood flows in the different parts (heart, lung, other organs). The influence of feedback mechanisms and the changes under workload and under different pathophysiological could be shown to be very well represented by the model. As exemplified for Enalapril, this model can be extended to a full PBPK/PD model and close the gap from PBPK approaches to predictive PBPK/PD simulations [5].
Conclusions: In conclusion, the developed physiologically-based model for the dynamics of the cardiovascular system is capable of simulating a broad range of relevant physiological conditions for healthy and diseased individuals. The model is able to cover the changes under workload, oxidative stress showing the detailed interplay of the different feedback mechanisms influencing the hemodynamics. The simulations were able to explain/represent different pathophysiological states in arterial and pulmonary hypertension.
References:
[1] Cain PA, Ahl R, Hedstrom E, Ugander M, Allansdotter-Johnsson A, Friberg P, et al. BMC Med Imaging. 2009;9:2.
[2] Hudsmith LE, Petersen SE, Francis JM, Robson MD, Neubauer S. J Cardiovasc Magn Reson. 2005;7(5):775-82.
[3] Ursino M. Interaction between carotid baroregulation and the pulsating heart: a mathematical model. Am J Physiol. 1998 Nov;275(5 Pt 2):H1733-47.
[4] Waxman AB. Prog Cardiovasc Dis. 2012 Sep;55(2):172-9.
[5] Claassen K, Willmann S, Eissing T, Preusser T, Block M. Front Physiol. 2013;4:4.
Reference: PAGE 22 () Abstr 2825 [www.page-meeting.org/?abstract=2825]
Poster: Other Drug/Disease Modelling