title: Characterization and Prediction of Cardiovascular Effects of Fingolimod and Siponimod Using a Systems Pharmacology Modeling Approach.
abstract: 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 (i.e., primary hemodynamic response variable) 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 analyzed using a recently developed systems cardiovascular pharmacology model, i.e. the CVS model; total peripheral resistance and heart rate were identified as the site of action for fingolimod. Next, the CVS model was interfaced with an S1P agonist pharmacokinetic-pharmacodynamic (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 hemodynamic 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.
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Nelleke
authors.initials: N
authors.lastname: Snelder
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Bart A
authors.initials: BA
authors.lastname: Ploeger
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Olivier
authors.initials: O
authors.lastname: Luttringer
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Rigel
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Webb
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: David
authors.initials: D
authors.lastname: Feldman
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Fumin
authors.initials: F
authors.lastname: Fu
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Beil
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Stanski
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands (N.S., B.A.P., M.D.); LAP&P Consultants BV, Leiden, The Netherlands (N.S., M.D.); Modeling and Simulation Department, Novartis, Basel, Switzerland (O.L., D.R.S.); Cardiovascular and Metabolism Research, Novartis Institutes for BioMedical Research (D.F.R., D.F., F.F., M.B., L.J.), and Cardiovascular Clinical Development (R.L.W.), Novartis Pharmaceuticals Corporation, East Hanover, New Jersey m.danhof@lacdr.leidenuniv.nl.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D019295:Computational Biology; D000068876:Fingolimod Hydrochloride / Q000493:pharmacokinetics / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008954:Models, Biological; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000378:metabolism
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; C578989:siponimod