OP27 A Phase 1 Study Evaluating the Bioequivalence of the Proposed Commercial and Clinical Formulations of Etrasimod 2mg, and the Effect of Food on the Pharmacokinetics of the Proposed Commercial Formulation in Healthy Volunteers
Lee, C.(1);Ramaiya, A.(1);Tang , Y.(1);Sapone, A.(2);Shan , K.(3);Randle, A.(4);Grundy, J.(1);
(1)Arena Pharmaceuticals- Inc., Nonclinical Dev & Clinical Pharmacology, San Diego, United States;(2)Arena Pharmaceuticals- Inc., Clinical Development, San Diego, United States;(3)Arena Pharmaceuticals- Inc., Biostatistics & Data Mgmt, San Diego, United States;(4)Arena Pharmaceuticals- Inc., Clinical Operations, San Diego, United States;
Etrasimod (ETR) is a once-daily, oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders including ulcerative colitis, Crohn’s disease, eosinophilic esophagitis, and atopic dermatitis. This study evaluated the single-dose bioequivalence of the proposed commercial and clinical formulations of ETR 2mg in the fasted state, and the effect of food on the pharmacokinetics of the proposed commercial formulation.
This 3-treatment, 3-period crossover Phase 1 study enrolled 18 healthy adults (18-55 years: 10 males/8 females). Participants were randomized to 6 treatment sequences (3 participants/sequence: ABC, BCA, CAB, ACB, BAC, CBA) consisting of Treatment A (single-dose ETR 2mg clinical formulation, fasted), Treatment B (single-dose ETR 2mg proposed commercial formulation, fasted), and Treatment C (single-dose ETR 2mg proposed commercial formulation, fed). Treatments were administered on Days 1, 10, and 19 to allow 8-day washout periods between treatments. In the fed state (Treatment C), all participants received an FDA-standard high-fat, high-calorie meal. Blood samples for determination of ETR concentration were collected at prespecified timepoints to 168 hours post dose. Analysis of variance was performed on log-transformed Cmax, AUC0-last, and AUC0-∞ values to determine geometric least squares mean ratios (GLSMR) of Test/Reference and associated 90% confidence intervals (CI) to assess bioequivalence and food effects. Safety and tolerability of ETR were also evaluated.
Bioequivalence: The 90% CI for the GLSMR of ETR Cmax and AUC plasma exposure measures, comparing the proposed commercial vs clinical formulations, were within the accepted 80%–125% range (GLSMR and 90% CI) for establishing bioequivalence (Table 1). Median Tmax for Treatments A and B were both 4 hours. Food Effect: The 90% CI for the GLSMR of ETR Cmax and AUC plasma exposure measures, comparing the proposed commercial formulation under fed vs fasted conditions, were within the accepted 80%–125% range for establishing no food effect (Table 2). Median Tmax for Treatment C was 6 hours. Safety and Tolerability: All treatment-emergent adverse events (AEs) were mild (except 1 moderate AE [headache]). One participant had an AE leading to study drug discontinuation. There were no serious AEs or deaths.
Based on results from this study, the proposed commercial and clinical formulations of ETR 2mg were bioequivalent in terms of rate and extent of absorption. No significant differences were demonstrated in ETR exposure for the proposed commercial formulation under fed and fasted conditions. All treatments were generally safe and well tolerated.