title: Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators.
abstract: BACKGROUND
  Sphingosine-1-phosphate (S1P) receptor modulators, of which one has received marketing approval and several others are in clinical development, display promising potential in the treatment of a spectrum of autoimmune diseases.
  
  
  METHODS
  Administration of S1P1 receptor modulators leads to functional receptor antagonism triggering sustained inhibition of the egress of lymphocytes from lymphoid organs. First-dose administration is associated with transient cardiovascular effects. We compiled and discussed available pharmacokinetic, pharmacodynamic, and safety data of selective and non-selective S1P receptor modulators that were investigated in recent years.
  
  
  CONCLUSIONS
  The safety profile of S1P receptor modulators is considered better than other classes of immunomodulators and was further improved by the development of up-titration regimens to mitigate first-dose effects. S1P receptor modulators display similar pharmacodynamic effects but have very different pharmacokinetic profiles. Drugs with a rapid elimination are of interest in case of opportunistic infections or pregnancy, whereas the need of re-initiation of up-titration in case of treatment interruption can present a challenge.
authors.affiliation: a Department of Clinical Pharmacology , Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
authors.forename: Pierre-Eric
authors.initials: PE
authors.lastname: Juif
authors.affiliation: b Department of Clinical Pharmacology and Toxicology , Universitätsspital Basel , Basel , Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kraehenbuehl
authors.affiliation: a Department of Clinical Pharmacology , Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D015195:Drug Design; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008214:Lymphocytes / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000187:drug effects* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D007155:Immunologic Factors; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: Autoimmune diseases; S1P1 receptor modulators; cardiodynamic effect; fingolimod; first dose; lymphocytes; ponesimod