Glaenzel, Ulrike, Jin, Yi, Nufer, Robert, Li, Wenkui, Schroer, Kirsten, Adam, Sylvie, van Marle, Sjoerd Peter, Legangneux, Eric, Borell, Hubert, James, Alexander David, Meissner, Axel, Camenisch, Gian P. and Gardin, Anne (2018) Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism. Drug metabolism and disposition, 46 (7). pp. 1001-1013. ISSN 1521-009X

Abstract

Siponimod, a next generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism and excretion of a single oral dose of [14C]siponimod
10 mg in four healthy male subjects. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds. Unchanged siponimod accounted for 57% of the total plasma radioactivity (AUC), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median Tmax: 4 h) and moderate distribution (Vz/F: 291 L). Siponimod was mainly cleared through biotransformation predominantly by oxidative metabolism. The mean apparent elimination half-life of siponimod in plasma was 56.6 h. Siponimod was excreted mostly in feces in the form of oxidative metabolites. The excretion of radioactivity was close to complete after 13 days. Based on the metabolite patterns, a phase II metabolite (M3) formed by glucuronidation of hydroxylated siponimod was the main circulating metabolite in plasma. However, in subsequent mouse ADME and clinical PK studies, a long-lived non-polar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. Furthermore, we conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. Selective inhibitors and recombinant enzyme results identified cytochrome P450 2C9 (CYP2C9) as the predominant contributor to the human liver microsomal biotransformation of siponimod, with minor contributions from CYP3A4 and other P450 enzymes.

Item Type:	Article
Keywords:	English
Date Deposited:	11 Sep 2018 00:45
Last Modified:	11 Sep 2018 00:45
URI:	https://oak.novartis.com/id/eprint/36042