Multiple-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites and the Pharmacodynamic and Pharmacokinetic
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ORIGINAL RESEARCH
Multiple-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites and the Pharmacodynamic and Pharmacokinetic Interactions with Pseudoephedrine, a Sympathomimetic Agent, in Healthy Subjects Jonathan Q. Tran
. Peijin Zhang . Susan Walker . Atalanta Ghosh .
Mary Syto . Xiaomin Wang . Sarah Harris . Maria Palmisano Received: August 7, 2020 / Accepted: September 5, 2020 Ó The Author(s) 2020
ABSTRACT Introduction: The aims of this study were to characterize the multiple-dose pharmacokinetics (PK) of ozanimod’s major active metabolites (CC112273 and CC1084037) and to evaluate the pharmacodynamic and PK interactions with pseudoephedrine (PSE). Methods: In this phase 1, single-center, randomized, double-blind, placebo-controlled study, 56 healthy adult subjects were randomized to receive either placebo or ozanimod once daily for 30 days (0.23 mg on days 1–4, 0.46 mg Digital Features To view digital features for this article go to https://doi.org/10.6084/m9.figshare.12918965. 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] S. Walker Apex Biostatistics, Inc, New Hill, NC, USA A. Ghosh Biometrics and Data Sciences, Bristol-Myers Squibb Company, Princeton, NJ, USA X. Wang Nonclinical Research and Development, BristolMyers Squibb Company, Princeton, NJ, USA S. Harris Translational Medicine, Bristol-Myers Squibb Company, Princeton, NJ, USA
on days 5–7, 0.92 mg on days 8–10, and 1.84 mg on days 11–30). On day 30, a single oral dose of PSE 60 mg was co-administered with placebo or ozanimod. Maximum time-matched change in systolic blood pressure (SBP) from baseline (day 29) following PSE administration on day 30 was calculated. Plasma PK parameters for ozanimod, CC112273, CC1084037, and PSE were estimated using noncompartmental methods. Results: Fifty-two subjects (92.9%) completed the study. Following multiple dosing, approximately 94% of circulating total active drug exposure was represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%). Exposures of CC112273 and CC1084037 were highly correlated. Mean maximum time-matched change from baseline for SBP was not significantly different between ozanimod ? PSE and placebo ? PSE. Ozanimod also had no effect on the PK of PSE. Co-administration of ozanimod with a single dose of PSE in healthy subjects was generally well tolerated. While CC112273 and CC1084037 selectively inhibited monoamine oxidase (MAO)-B in vitro, both active metabolites do not inhibit platelet MAOB activity in vivo. Conclusion: Concomitant administration of ozanimod with PSE, a sympathomimetic agent, did not potentiate the effects on blood pressure. Trial Registration: NCT03644576.
Adv Ther
Keywords: Drug interaction; MAO-B; Monoamine oxidase; Ozanimod; Pharmacokinetics; Pseudoephedrine Key Summary Points Why carry out this study? In vitro data showed that ozanimod’s major active metabolites, CC112273 and CC1084037, selec
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