title: Modeling the Effect of the Selective S1P1Receptor Modulator Ponesimod on Subsets of Blood Lymphocytes.
abstract: This analysis aimed at describing the effect of the selective sphingosine-1-phosphate receptor 1 modulator ponesimod on lymphocyte subsets in peripheral blood. As the involvement of different lymphocyte subsets varies among different autoimmune diseases, characterizing the effect of ponesimod on these may be beneficial in better understanding treatment effects.
  
  
  
  Three phase 1 clinical studies in healthy human subjects were pooled. Non-linear mixed-effects modeling techniques were used to study the effect of ponesimod on lymphocyte subsets such as B cells, T helper cells, T cytotoxic cells, and natural killer cells in a qualitative and quantitative manner.
  
  
  
  Indirect-response Imaxmodels including circadian variation best described the effect of ponesimod on lymphocyte subsets. B cells and T helper cells were shown to be more affected compared to T cytotoxic cells with respect to the maximum possible reduction (100% for B and T helper cells, 95% for T cytotoxic cells) and the concentration required to reach half the maximum effect. Inter-individual variability was found to be larger for T cytotoxic compared to T helper, and B cells.
  
  
  
  These first models for ponesimod on the level of lymphocyte subsets offer a valuable tool for the analysis and interpretation of results from ponesimod trials in autoimmune diseases.
authors.affiliation: Department of Clinical Pharmacy, Saarland University, Saarbrücken, Germany. Dominik.Lott@actelion.com.|Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123, Allschwil, Switzerland. Dominik.Lott@actelion.com.
authors.forename: Dominik
authors.initials: D
authors.lastname: Lott
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123, Allschwil, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Krause
authors.affiliation: Department of Global Clinical Science and Epidemiology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Seemayer
authors.affiliation: Department of Translational Science Biology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Strasser
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.affiliation: Department of Clinical Pharmacy, Saarland University, Saarbrücken, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lehr
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002940:Circadian Rhythm; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; C550169:ponesimod
keywords: B cells; PK/PD modeling; T cells; lymphocyte subsets; sphingosine-1-phosphate receptor