Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism and excretion of ozanimod was investigated following a single oral dose of 1.0 mg C-ozanimod hydrochloride to six healthy subjects. In vitro experiments were conducted to understand the metabolic pathways and enzyme involved in the metabolism of ozanimod and its active metabolites. The total mean recovery of the administered radioactivity was ~63%, with ~26% and ~37% recovered from urine and feces, respectively. Based on exposure, the major circulating components were active metabolite CC112273 and inactive metabolite RP101124 and together accounted for 50% of the circulating total radioactivity exposure while ozanimod accounted for 6.7% of the total radioactive exposure. Ozanimod was extensively metabolized, with 13 metabolites identified including 2 major active metabolites (CC112273 and CC1084037) and 1 major inactive metabolite (RP101124) in circulation. Ozanimod is metabolized by three primary pathways including aldehyde dehydrogenase and alcohol dehydrogenase, cytochrome P450 (CYP) isoforms 3A4, 1A1, and reductive metabolism by gut microflora. The primary metabolite RP101075 is further metabolized to form major active metabolite CC112273 by monoamine oxidase B which further undergoes reduction by carbonyl reductases (CBR) to form CC1084037 or CYP2C8 mediated oxidation to form RP101509. CC1084037 is oxidized rapidly to form CC112273 by aldo-keto reductase (AKR) 1C1/1C2, and/or 3β- and 11β-hydroxysteroid dehydrogenase (HSD) and this reversible oxido-reduction between two active metabolites favors CC112273. Ozanimod example illustrates the need for conducting timely radiolabeled human ADME studies for characterization of disproportionate metabolites and assessment of exposure coverage during drug development. Absorption, metabolism, and excretion of ozanimod was characterized in humans and the enzymes involved in complex metabolism were elucidated. Disproportionate metabolites were identified, and the activity of these metabolites were determined.
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