Effects of High- and Low-Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator

Abstract

Introduction: Ozanimod (RPC1063) is an oral, selective sphingosine 1-phosphate (S1P) 1 and 5 receptor modulator in clinical development for the treatment of relapsing multiple sclerosis and inflammatory bowel disease. Since food has the potential to significantly influence the rate and extent of drug absorption, we designed and conducted a food-effect study with ozanimod. Methods: The objective of this study was to characterize the effects of high-fat and low-fat meals on the pharmacokinetics (PK) of a single oral dose of ozanimod in healthy adult subjects. This was a randomized, open-label, 3-period, 6-sequence, crossover study. Twenty-four healthy adult subjects were enrolled to receive a single 1-mg oral dose of ozanimod under 3 different conditions separated by washout periods of 7 days: fasted (treatment A), with a standard FDA high-fat meal (treatment B), and with a low-fat meal (treatment C). PK parameters for ozanimod and its two active metabolites (RP101988 [major] and RP101075 [minor]) were calculated. Point estimates and 90% confidence intervals (CIs) about the geometric mean ratio between treatments for maximum concentration (Cmax) and overall exposure (AUC0-inf or AUC0-last) were determined using linear mixed-effects models. Results: Twenty subjects completed both treatments A and B and 23 subjects completed both treatments A and C and provided PK data for the pair-wise comparison of fed vs fasted. The 90% CIs between fed (high-fat or low-fat) and fasted treatments for the Cmax and AUC0-inf of ozanimod and RP101988 were all within the no-effect boundary of 0.80 to 1.25. For the minor metabolite RP101075, the 90% CIs between high-fat and fasted for AUC0-last and the 90% CIs between low-fat and fasted for Cmax and AUC0-last were within the no-effect boundary. While the 90% CI between high-fat and fasted treatments for RP101075 Cmax (0.76 to 0.88) fell outside the lower bound of the no-effect boundary, this decrease was not considered to be clinically meaningful. Median time to reach Cmax (Tmax) for ozanimod was delayed following a high-fat meal (12 hours) compared to fasted and lowfat meal conditions (8 hours), but the range (6 to 12 hours) was the same. Mean elimination half-life (t1/2) values for ozanimod and its active metabolites ranged from 17-21 hours and were similar across all 3 treatments. Overall, single oral doses of 1 mg ozanimod were considered generally well tolerated. Conclusion: Ozanimod may be taken with or without food.