Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans

• Published in: Xenobiotica Vol. 45; no. 2; pp. 139 - 149
• Main Authors: Reyes, Maribel, Hoch, Matthias, Brossard, Patrick, Wagner-Redeker, Winfried, Miraval, Tommaso, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.02.2015; Informa Healthcare
• Subjects: Administration, Oral; Humans; Male; Mass balance; metabolism; Middle Aged; ponesimod; Receptors, Lysosphingolipid - chemistry; Receptors, Lysosphingolipid - metabolism; Scintillation Counting; sphingosine-1-phosphate receptor; Thiazoles - adverse effects; Thiazoles - chemistry; Thiazoles - metabolism; Thiazoles - pharmacokinetics; Mass balance; ponesimod; sphingosine-1-phosphate receptor; metabolism
• ISSN: 0049-8254; 1366-5928; 1366-5928
• DOI: 10.3109/00498254.2014.955832

Abstract 1. Ponesimod [(R)-5-[3-chloro-4-(-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one] is an orally administered, selective S1P1 receptor modulator that blocks the egress of lymphocytes from lymphoid organs and reduces the availability of circulating effector T/B-cells. 2. The mass balance, pharmacokinetics and metabolism of 40 mg 14C-ponesimod were investigated in six healthy male subjects. The total radioactivity in whole blood, plasma, urine, faeces and expired CO2 was determined by liquid scintillation counting. Metabolite profiling was performed by high-performance liquid chromatography and detection by mass spectrometry. 3. The majority of the radioactivity (% of administered dose) was recovered in faeces (57.3-79.6%), followed by urine (10.3-18.4%) and a small proportion in CO2 from expired air (0.6-1.9%). The average cumulative recovery (mass balance) of 14C-associated radioactivity in faeces and urine was 77.9% of the administered dose. Unchanged ponesimod made up 25.9% of total radioactivity in faeces; none was detected in urine. Ponesimod was extensively metabolised and two pharmacologically inactive metabolites, M12 (ACT-204426) and M13 (ACT-338375), were detected in the circulation. M12 corresponded to 8.1% and M13 to 25.7% of the total drug-related radioactive exposure (AUC0-∞) in plasma. M12 was highly abundant in faeces (22.3% of total radioactivity) and to a smaller extent in urine (2.5% of total radioactivity).