Single-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites Alone and in Combination with Gemfibrozil, Itraconazole, or Rifampin in Healthy Subjects: A Randomized, Parallel-Group, Open-Label Study.

Abstract

The aims of this study were to characterize the single-dose pharmacokinetics (PK) of the major active metabolites of ozanimod, CC112273 and CC1084037, and to evaluate the effect of gemfibrozil (a strong inhibitor of cytochrome P450 [CYP] 2C8), itraconazole (a strong inhibitor of CYP3A and P-glycoprotein [P-gp]), and rifampin (a strong inducer of CYP3A/P-gp and moderate inducer of CYP2C8) on the single-dose PK of ozanimod and its major active metabolites in healthy subjects. This was a phase1, randomized, parallel-group, open-label study with two parts. In part1, 40 subjects were randomized to receive a single oral dose of ozanimod 0.46mg (groupA, n = 20) or oral doses of gemfibrozil 600mg twice daily for 17days with a single oral dose of ozanimod 0.46mg on day4 (groupB, n = 20). In part2, 60 subjects were randomized to receive a single oral dose of ozanimod 0.92mg (groupC, n = 20), oral doses of itraconazole 200mg once daily for 17days with a single oral dose of ozanimod 0.92mg on day4 (groupD, n = 20), or oral doses of rifampin 600mg once daily for 21days with a single oral dose of ozanimod 0.92mg on day8 (groupE, n = 20). Plasma PK parameters for ozanimod, CC112273, and CC1084037 were estimated using noncompartmental methods. Dose-proportional increases in maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) were observed for ozanimod, CC112273, and CC1084037. The mean terminal elimination half-life (t1/2) for ozanimod was approximately 20-22h while the mean t1/2 for CC112273 and CC1084037 were approximately 10days. CC112273 and CC1084037 exposures were highly correlated with or without interacting drugs. Itraconazole increased ozanimod AUC by approximately 13% while rifampin reduced ozanimod AUC by approximately 24%, suggesting a minor role of CYP3A and P-gp in the overall disposition of ozanimod. Gemfibrozil increased the AUC for CC112273 and CC1084037 by approximately 47% and 69%, respectively. Rifampin reduced the AUC for CC112273 and CC1084037, primarily via CYP2C8 induction, by approximately 60% and 55%, respectively. Ozanimod's major active metabolites, CC112273 and CC1084037, exhibited similar single-dose PK properties and their exposures were highly correlated. CYP2C8 is one of the important enzymes in the overall disposition of CC112273 and subsequently its direct metabolite CC1084037. Clinical trial: NCT03624959.