Single-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites Alone and in Combination with Gemfibrozil, Itr
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ORIGINAL RESEARCH
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 Jonathan Q. Tran
. Peijin Zhang . Atalanta Ghosh .
Liangang Liu . Mary Syto . Xiaomin Wang . Maria Palmisano Received: July 8, 2020 Ó The Author(s) 2020
ABSTRACT Introduction: 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. Methods: This was a phase 1, randomized, parallel-group, open-label study with two parts. In part 1, 40 subjects were randomized to receive a single oral dose of ozanimod 0.46 mg (group A, n = 20) or oral doses of gemfibrozil 600 mg twice daily for 17 days with a single oral dose of Digital Features To view digital features for this article go to https://doi.org/10.6084/m9.figshare.12789758. J. Q. Tran (&) P. Zhang M. Syto M. Palmisano Clinical Pharmacology and Pharmacometrics and Research and Early Development, Bristol-Myers Squibb Company, Princeton, NJ, USA e-mail: [email protected] A. Ghosh L. Liu Biometrics and Data Science, Bristol-Myers Squibb Company, Princeton, NJ, USA X. Wang Bristol-Myers Squibb Company, Nonclinical Research and Development, Princeton, NJ, USA
ozanimod 0.46 mg on day 4 (group B, n = 20). In part 2, 60 subjects were randomized to receive a single oral dose of ozanimod 0.92 mg (group C, n = 20), oral doses of itraconazole 200 mg once daily for 17 days with a single oral dose of ozanimod 0.92 mg on day 4 (group D, n = 20), or oral doses of rifampin 600 mg once daily for 21 days with a single oral dose of ozanimod 0.92 mg on day 8 (group E, n = 20). Plasma PK parameters for ozanimod, CC112273, and CC1084037 were estimated using noncompartmental methods. Results: 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 20–22 h while the mean t1/2 for CC112273 and CC1084037 were approximately 10 days. 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.
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