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, Jonathan Q Tran, Peijin Zhang, Susan Walker, Atalanta Ghosh, Mary Syto, Xiaomin Wang, Sarah Harris, Maria Palmisano

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 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 MAO-B activity in vivo.

Conclusion: Concomitant administration of ozanimod with PSE, a sympathomimetic agent, did not potentiate the effects on blood pressure.

Trial registration: NCT03644576.

Keywords: Drug interaction; MAO-B; Monoamine oxidase; Ozanimod; Pharmacokinetics; Pseudoephedrine.

Figures

Fig. 1
Fig. 1
Mean (SD) plasma concentration–time profiles for ozanimod, CC112273, and CC1084037 over the 24-h dosing interval following ozanimod dosing initiation on day 1 (0.23 mg; a), dose escalation on day 5 (0.46 mg; b), and after 28 days of repeated dosing (1.84 mg, c); N = 28. SD standard deviation
Fig. 2
Fig. 2
Relationship of CC112273 and CC1084037 Cmax and AUC0–24 on day 28. AUC0–24 area under the concentration–time curve from 0 to 24 h postdose, Cmax maximum observed concentration
Fig. 3
Fig. 3
Mean (SD) PSE plasma concentration–time profiles for a single dose of PSE 60 mg when co-administered with ozanimod or placebo. PSE pseudoephedrine
Fig. 4
Fig. 4
Change from baseline in platelet’s MAO-B activity versus plasma concentration for CC112273 (a) or CC1084037 (b). CI confidence interval, MAO monoamine oxidase

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