Karina Claassen (1), Stefan Willmann (2), Thomas Eissing (2), Tobias Preusser (1, 3), Michael Block (2)
(1) Jacobs University Bremen, School of Engineering and Science, Campus Ring 1, 28759 Bremen, Germany; (2) Bayer Technology Services GmbH, Technology Development, Enabling Technologies, Computational Systems Biology, Building 9115, 51368 Leverkusen, Germany; (3) Fraunhofer MEVIS, Universitätsallee 29, 28359 Bremen, Germany
Objectives: This work is aimed to develop a whole body physiologically based pharmacokinetic (wb PBPK) model including a dynamic circulation model and the renin-angiotensin-aldosterone system (RAAS). Furthermore a model for detailed representation of the arterial blood pressure (BP) is developed.
Methods: The PBPK model was established by usage of PK-Sim® and MoBi® based on data for physiological factors determining the RAAS and the circulation. In a first step a PBPK model was developed and physiological data of the RAAS [1-4] have been included. This results in a coupled wb PBPK model containing the temporal evolution for the main RAAS actors angiotensinogen, angiotensin 1 and 2, angiotensin 2 receptor type 1, aldosterone, renin and angiotensin converting enzyme. The influence of xenobiotics on this hormone system involved in the regulation of BP is discussed in detail. In a second step a mechanistic representation of the mean arterial blood pressure (MAP) was build based on available data [5-7] and then integrated into a wb PBPK model. Different pathological states leading to hypertension or hypotension were investigated by this pharmacodynamic (PD) model and compared to observed behavior. The impact of different physiological conditions on the MAP will be shown exemplarily.
Results: The results show in detail that the RAAS model is able to describe the circulating plasma hormone levels with sufficient agreement to experimental data. Further development of the blood pressure regulation model led to a very accurate representation of the typical behavior of the circulation and the changes in case of pathological conditions. Different realistic BP scenarios like hypertension or hypotension could be described by this approach and the modeled effects of the main physiological factors influencing the MAP are in very good agreement with knowledge gained from literature.
Conclusions: The wb PBPK model of the RAAS is able to represent the pharmacokinetics of drugs interacting with RAAS and the hormone system sufficiently well, indicating a reasonable description of the underlying physiological processes. Furthermore, the accurate prediction of the BP changes by the PD model under different healthy and pathological conditions indicates a good representation of the BP regulation. Next steps will be the coupling of both models, which could lead to a mechanistic representation of the PBPK-PD relationship in cardiovascular diseases and thus help to facilitate dose and dosing regimen decisions in the area of cardiovascular diseases.
References:
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[4] Wishart DS, Knox C, Guo AC, et al.: HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res. 2009;37(Database issue):25.
[5] Valentin J: Basic anatomical and physiological data for use in radiological protection: reference values: ICRP Publication 89. Annals of the ICRP. 2002 September-December 2002;Volume 32(Issues 3-4):Pages 1-277.
[6] Klabunde RE: editor. Cardiovascular Physiology Concepts. Philadelphia: Lippincott Williams & Wilkins; 2005.
[7] Hansen TW, Thijs L, Li Y, et al.: Prognostic value of reading-to-reading blood pressure variability over 24 hours in 8938 subjects from 11 populations. Hypertension. 2010 Apr;55(4):1049-57.
Reference: PAGE 21 () Abstr 2536 [www.page-meeting.org/?abstract=2536]
Poster: New Modelling Approaches