Characterization and Prediction of Cardiovascular Effects of Fingolimod and Siponimod Using a Systems Pharmacology Modeling Approach

Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model to identify the site of action of S1P receptor agonists, and to predict, in a quantitative manner, the cardiovascular effects of novel S1P receptor agonists in vivo. The cardiovascular effects of once daily fingolimod (0, 0.1, 0.3, 1, 3 and 10 mg/kg) and siponimod (3 and 15 mg/kg) were continuously recorded in spontaneously hypertensive rats and Wistar-Kyoto rats. The results were analysed using a recently developed systems cardiovascular pharmacology (CVS) model; total peripheral resistance (TPR) and heart rate (HR) were identified as the site of action for fingolimod. Next the CVS model was interfaced with a S1P agonist PKPD model. This combined model adequately predicted in a quantitative manner the cardiovascular effects of siponimod using in vitro binding assays. In conclusion, the combined CVS and S1P agonist PKPD model adequately describes the haemodynamic effects of S1P receptor agonists in rats and constitutes a basis for the prediction, in a strictly quantitative manner, of the cardiovascular effects of novel S1P receptor agonists.