Modeling the Effect of the Selective S1P1 Receptor Modulator Ponesimod on Subsets of Blood Lymphocytes

• Published in: Pharmaceutical research Vol. 34; no. 3; pp. 599 - 609
• Main Authors: Lott, Dominik, Krause, Andreas, Seemayer, Christian A., Strasser, Daniel S., Dingemanse, Jasper, Lehr, Thorsten
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.03.2017
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Medical Law; Pharmacology/Toxicology; Pharmacy; Research Paper; lymphocyte subsets; PK/PD modeling; sphingosine-1-phosphate receptor; B cells; T cells
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-016-2087-x

Purpose 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. Methods 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. Results Indirect-response I max models 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. Conclusion 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.