Towards predictive cardiovascular safety : a systems pharmacology approach

Snelder, N. (2014)

Doctoral Thesis

Cardiovascular safety issues related to changes in blood pressure, arise frequently in drug development. In the thesis __Towards predictive cardiovascular safety __ a systems pharmacology approach__, a system-specific model is described to quantify drug effects on the interrelationship between mean arterial pressure, cardiac output, heart rate, stroke volume and total peripheral resistance in rats. The developed model can be used to quantify and predict the dynamic changes in the cardiovascular system (CVS) and elucidate the mechanism of action of novel compounds. An ultimate application of this system-specific CVS model would be to facilitate the anticipation of the clinical response based on preclinical data for newly developed compounds. Furthermore, the developed system-specific CVS model was combined with receptor models to quantify and predict the cardiovascular effects of the sphingosine 1-phosphate (S1P) receptor agonists, fingolimod-phosphate (fingolimod-P)and siponimod, in rats. This systems pharmacology model provided a quantitative understanding of the cardiovascular effects of fingolimod-P and siponimod and can be applied to predict the cardiovascular effects of other S1P receptor agonists with different selectivity profiles in rats. Ultimately, it may constitute a basis for prediction of cardiovascular effects of S1P receptor agonists in humans

• Systems pharmacology
• Mechanism-based
• Population approach
• Cardiovascular
• Heart rate
• Blood pressure

• All authors: Snelder, N.
• Supervisor: Danhof, M.; Stanski, D.R.
• Co-supervisor: Ploeger, B.A.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Science, Leiden University
• Date: 2014-06-25
• Sponsorship: Novartis, LAP&P Consultants BV