E0361 - Pharmacokinetics, Safety, and Tolerability of Etrasimod: Results From a Phase 1 Drug-Drug Interaction Study in Healthy Volunteers

Caroline A. Lee, PhD, Yong Tang, PhD, Leonel Villa-Caballero, MD, PhD, Kevin Shan, 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. ETR has the potential for drug-drug interaction with CYP2C8, CYP2C9, and CYP3A4 when coadministered with inhibitors or inducers of these enzymes. This open-label Phase 1 study evaluated the PK and safety of ETR in the presence of fluconazole, gemfibrozil, or rifampin.

Methods: Fifty-six healthy volunteers (18-55 years) were assigned to 1 of 3 treatment groups, each with 2 dosing periods separated by a 7-day washout. On Day 1 (Period 1), Groups A and B received a single dose of ETR 1mg whereas Group C received a single dose of ETR 2mg. From Days 8–22 (Period 2), Groups A and B received fluconazole once daily (QD) (400mg on Day 8; 200mg on Days 9–22) and gemfibrozil 600mg twice daily, respectively, and a single dose of ETR 1mg on Day 12, whereas Group C received rifampin 600mg QD and a single dose of ETR 2mg on Day 15. Primary endpoints were plasma C_max, AUC_0-168h, and AUC_0-∞ of ETR in the presence and absence of fluconazole, gemfibrozil, or rifampin. Log-transformed primary PK parameters for ETR were compared using analysis of variance with treatment as fixed effect and participant as random effect.

Results: In the presence of fluconazole or gemfibrozil, there was little impact on ETR C_max, but AUC_0-168h and AUC_0-∞ were mildly-to-moderately increased (Table). Geometric mean t_1/2 of ETR increased from 42 to 87 hours in the presence of fluconazole and from 45 to 70 hours in the presence of gemfibrozil. When administered in the presence vs absence of rifampin, ETR C_max only slightly increased while AUC_0-168h and AUC_0-∞ moderately decreased. Geometric mean t_1/2 of ETR decreased by ~50% in the presence of rifampin. All treatments were generally well tolerated. All treatment-emergent AEs were mild or moderate. One participant discontinued the study due to AEs. No abnormalities were found in laboratory parameters, vital signs, or 12-lead electrocardiograms.

Discussion: These results are consistent with CYP2C8, CYP2C9, and CYP3A4 being involved in ETR metabolism with no single enzyme appearing to dominate its elimination. The involvement of multiple CYP isoforms reduces the likelihood of ETR having a clinically relevant drug interaction, particularly when only a single CYP isoform is strongly or moderately inhibited/induced by a coadministered drug.



Disclosures:


Caroline A. Lee, PhD, Yong Tang, PhD, Leonel Villa-Caballero, MD, PhD, Kevin Shan, PhD, Andrenika Randle, , John S. Grundy, PhD. E0361 - Pharmacokinetics, Safety, and Tolerability of Etrasimod: Results From a Phase 1 Drug-Drug Interaction Study in Healthy Volunteers, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.