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

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 (AUC_0–∞) 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).

• Mass balance
• metabolism
• ponesimod
• sphingosine-1-phosphate receptor

Acknowledgements

The authors would like to thank Christopher Kohl for the pre-clinical work performed with ponesimod, Wenting Zhang-Fu and Kasra Shakeri-Nejad for their medical input and assessment and Michael Seiberling, Covance Switzerland, for the supervision of the clinical study conduct.

Declaration of interest

Actelion Pharmaceuticals Ltd provided the funding for this clinical trial. Matthias Hoch and Jasper Dingemanse are employees of Actelion Pharmaceuticals Ltd. Maribel Reyes and Patrick Brossard are former employees of Actelion Pharmaceuticals Ltd. Winfried Wagner-Redeker is an employee of Swiss Bioanalytics, Birsfelden, Switzerland. Tommaso Miraval is a former employee of Swiss Bioanalytics, Birsfelden, Switzerland.