Poster: Drug/Disease modeling - Absorption & PBPK
II-32 Development of a Cardio-Vascular Systems Pharmacology Platform
Katrin Coböken (1), Donato Teutonico (1), Thomas Gaub (1), Frank Kramer (2), Jörg Lippert (2), Michaela Meyer (1), Heiner Post (2), Walter Schmitt (2), Hubert Trübel (2), Rolf Burghaus (2), and Thomas Eissing (1)
(1) Bayer Technology Services, Leverkusen, Germany, (2) Bayer HealthCare, Wuppertal, Germany
Objectives: Mathematical modelling and simulation techniques provide an efficient approach in analyzing and predicting complex physiological systems and medical conditions. During the last decades, such tools have been applied to the modeling of the cardiovascular system with increasing model complexity. The objective of this project was to develop a computational framework integrating physiological knowledge as well as experimental data from all the different drug development stages capable of predicting cardiovascular parameters relevant in drug development.
Methods: We developed a Cardio Vascular Systems Pharmacology Platform that includes a detailed description of relevant hemodynamic processes along with their vegetative and hormonal regulation. The model was built in PK-Sim and MoBi4) by integrating different literature models1),2),3) and is parameterized for describing a healthy adult subject.
Results: The platform is able to predict physiological behaviors in a healthy subject and is validated in different perturbation scenarios including beta-blocker administration, tilt test and exercise. Model outputs are compared to the most relevant cardiac measurements including left ventricular pressure-volume relationship, mean arterial blood pressure, heart rate and cardiac output. The simulation of beta-blocker effects was used as proof-of-concept to simulate pharmacological intervention.
Conclusions: The cardiovascular model is able to describe the behavior of a healthy human cardiovascular system at rest, during exercise and after drug administration. The model structure is compatible with physiologically-based pharmacokinetic (PBPK) models allowing for the integrated dynamic description of concentration-dependent pharmacological effects on the cardiovascular system and, vice versa, pharmacodynamic effects influencing the pharmacokinetics. Further extensions of the platform will include the implementation of additional regulation mechanisms relevant for other drug classes as well as the parameterization of relevant disease populations.
References:
[1] Heldt T. Computational Models of Cardiovascular Response to Orthostatic Stress. PhD thesis Harvard–MIT, Division of Health Science & Technology (2005).
[2] Ursino M. Interaction between carotid baroregulation and the pulsating heart: a mathematical model. Am J Physiol. (1998)
[3] Klotz S. et al. Single-beat estimation of end-diastolic pressure-volume relationship: a novel method with potential for noninvasive application. Am J Physiol Heart Circ Physiol. (2006)
[4] Eissing T. et al. A computational system biology software platform for the multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front. Physio. (2011)