P208 Effect of coadministration of etrasimod on the pharmacokinetics and pharmacodynamics of a monophasic oral contraceptive

Abstract

<h3>Introduction</h3> Etrasimod (ETR) is a once-daily (QD), oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders including inflammatory bowel disease (IBD). At diagnosis, ~50% of patients with IBD are &lt;35 years old. Oral contraceptives (OC) are the most common birth control among women in the US. It’s important to ensure an IBD therapy does not impact the pharmacokinetic (PK) or pharmacodynamic (PD) performance of an OC. This study evaluated the effect of coadministration of ETR on the PK and PD performance of a monophasic OC. <h3>Methods</h3> This open-label Phase 1 study enrolled 21 premenopausal healthy females (18-40 years). On Days 1–21 of Period 1 (Days 1–28), participants received OC containing 30mcg ethinylestradiol (EE) and 50mcg levonorgestrel (LVG). On Day 23, participants initiated ETR 2mg QD such that steady-state concentrations were achieved by Day 28 and thereafter. On Days 29–49 of Period 2 (Days 29–50), OC was coadministered with ETR 2mg QD. Samples for measuring the pharmacologically active components of the OC (EE and LVG) were collected over 24 hours on Days 21 and 49. Log-transformed primary PK parameters were calculated and compared using analysis of variance with treatment as fixed effect and participant as random effect. PD markers (follicle-stimulating hormone [FSH], luteinizing hormone [LH], estradiol, progesterone) were measured at baseline (Days 1 and 29) and throughout Periods 1 and 2. Sex hormone–binding globulin (SHBG) levels were measured on Days 1, 21, 29, and 49. Largest ovarian follicle size measured by transvaginal ultrasound (TVUS) and Hoogland score were measured on Days 1, 11, 29, and 39. <h3>Results</h3> Only minor-to-mild increases in EE and LVG C_max,ss and AUC_tau,ss exposure measures were observed when the OC was coadministered with ETR vs when the OC was administered alone (<b>Table</b>). These changes were not considered clinically relevant. Markers of ovarian activity (FSH, LH, estradiol, progesterone, SHBG, TVUS/Hoogland score) demonstrated no clinically relevant impact of coadministration of ETR on the PD performance of the OC. All treatments were generally well tolerated. Most treatment-emergent adverse events (AEs) were mild (grade 1) or moderate (grade 2); 2 participants had severe (grade 3) AEs (attributed to the OC). No abnormalities in laboratory parameters, vital signs, or 12-lead electrocardiogram were noted. <h3>Conclusions</h3> The PK and PD performance of the monophasic OC was not altered to a clinically relevant extent; thus contraceptive efficacy was maintained during coadministration with ETR. ETR and the monophasic OC, administered alone or in combination, were generally well tolerated.