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 (ADME) of a single 10-mg oral dose of [14C]siponimod in four healthy men. 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 (area under the concentration-time curve), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median Tmax: 4 hours) 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 hours. 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 pharmacokinetic studies, a long-lived nonpolar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. We further conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. The selective inhibitor 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 cytochrome P450 enzymes.
Highlights
Siponimod (BAF312; Novartis Pharma AG, Basel, Switzerland), a next-generation sphingosine-1-phosphate (S1P) receptor modulator, is currently being evaluated for the treatment of secondary progressive multiple sclerosis (SPMS)
The internalization of S1P1 receptors renders lymphocytes unresponsive to S1P, depriving them of an obligatory signal to egress from the lymph nodes and recirculate into the central nervous system (CNS), subsequently reducing neuroinflammation (Matloubian et al, 2004)
A total of 22 pharmacokinetic blood samples were collected before dose administration* and at 1, 2*, 4*, 6*, 8, 12, 16*, 24, 36*, 48, 72*, 96, 120*, 144, 168*, 192, 216, 240*, 312, 480, and 816 hours after dose administration into ethylenediaminetetraacetic acid (EDTA)-containing vacuum tubes by direct venipuncture or by an indwelling cannula inserted in a forearm vein
Summary
Siponimod (BAF312; Novartis Pharma AG, Basel, Switzerland), a next-generation sphingosine-1-phosphate (S1P) receptor modulator, is currently being evaluated for the treatment of secondary progressive multiple sclerosis (SPMS). S1P signaling pathways play a role in multiple sclerosis pathophysiology, and the therapeutic potential of S1P receptor modulation in multiple sclerosis treatment has been demonstrated using fingolimod (Gilenya), a functional antagonist of S1P1 receptors (Brinkmann et al, 2002; Baumruker et al, 2007; Cohen et al, 2010; Kappos et al, 2010), and siponimod (Selmaj et al, 2013; Kappos et al, 2016, 2018). S This article has supplemental material available at dmd.aspetjournals.org. Sphingosine-1-phosphate receptors are widely expressed in the body, including in lymphocytes and neural cells such as oligodendrocytes and astrocytes (Brinkmann, 2007). Compared with the first-generation S1P receptor modulators, siponimod does not require phosphorylation in vivo
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