E0362 - A Phase 1 Drug Interaction Study Evaluating the Effects of Itraconazole on the Pharmacokinetics, Safety, and Tolerability of Etrasimod in Healthy Volunteers

Caroline A. Lee, PhD, Atulkumar Ramaiya, PhD, Yong Tang, PhD, Anna Sapone, MD, PhD, Kye Gilder, PhD, Andrenika Randle, , John S. Grundy, PhD
Arena Pharmaceuticals, a wholly-owned subsidiary of Pfizer Inc., San Diego, CA

Introduction: Etrasimod (ETR), is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator in development for the treatment of several immune-mediated inflammatory disorders including ulcerative colitis, Crohn’s disease, eosinophilic esophagitis, atopic dermatitis, and alopecia areata. ETR is a substrate of cytochrome P450 (CYP)2C8, CYP2C9, and CYP3A4, and to a minor extent, CYP2C19 and CYP2J2. ETR was previously evaluated in the presence and absence of fluconazole (moderate inhibitor of CYP2C9 and CYP3A4; strong inhibitor of CYP2C19). ETR exposure measures (AUC_0-168h and AUC_0-∞) increased moderately up to 84% in the presence vs absence of fluconazole, likely due to inhibition of both CYP2C9 and CYP3A4. To determine the relative contribution of CYP3A4, the pharmacokinetics (PK) and safety of ETR in the presence of itraconazole (strong inhibitor of CYP3A4) were evaluated in this open-label Phase 1 study.

Methods: Eighteen healthy male and female volunteers (18-55 years) received a single dose of ETR 1mg on Day 1. Starting on Day 10, participants received 200mg itraconazole solution (10mg/mL) once daily for 13 days and a single dose of ETR 1mg on Day 14. Primary endpoints were plasma C_max, AUC_0-last, and AUC_0-∞ of ETR in the presence and absence of itraconazole. Log-transformed primary PK parameters for ETR were compared using analysis of variance with treatment as fixed effect and participant as random effect.

Results: The presence of itraconazole had little impact on single-dose peak exposure (C_max) of ETR, but mildly increased total exposure measures (AUC_0-last and AUC_0-∞) of ETR by up to 32% (Table). These changes were not considered clinically relevant. Geometric mean t_1/2 of ETR also mildly increased from 37 to 44 hours in the presence of itraconazole. All treatments were generally well tolerated. All treatment-emergent adverse events were mild. No abnormalities in laboratory parameters, vital signs, or 12-lead electrocardiogram assessments were noted.

Discussion: The results of this study demonstrate that CYP3A4 is one of several CYP isoforms, along with CYP2C8 and CYP2C9, primarily involved in the disposition of ETR. The involvement of multiple CYP isoforms reduces the likelihood of ETR having a clinically relevant drug interaction, particularly in cases where only a single CYP isoform is strongly or moderately inhibited/induced by a coadministered drug.



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Caroline A. Lee, PhD, Atulkumar Ramaiya, PhD, Yong Tang, PhD, Anna Sapone, MD, PhD, Kye Gilder, PhD, Andrenika Randle, , John S. Grundy, PhD. E0362 - A Phase 1 Drug Interaction Study Evaluating the Effects of Itraconazole on the Pharmacokinetics, Safety, and Tolerability of Etrasimod in Healthy Volunteers, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.