P207 Effects of fluconazole, gemfibrozil, and rifampin on the pharmacokinetics, safety, and tolerability of etrasimod

Caroline Lee,John S Grundy,Andrenika Randle,Leonel Villa-Caballero,Yong Tang,Kevin Shan,Carly Taylor

doi:10.1136/gutjnl-2022-bsg.261

Abstract

<h3>Introduction</h3> Etrasimod (ETR), a once-daily (QD), oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders, is a substrate of cytochrome P450 (CYP)2C8, CYP2C9, and CYP3A4, and to a minor extent, CYP2C19 and CYP2J2. ETR has the potential for drug-drug interaction (DDI) with CYP2C8, CYP2C9, and CYP3A4 when coadministered with inhibitors or inducers of these enzymes. This open-label Phase 1 study evaluated the pharmacokinetics (PK) and safety of ETR in the presence of fluconazole (moderate CYP2C9 and CYP3A4 inhibitor; strong CYP2C19 inhibitor), gemfibrozil (strong CYP2C8 inhibitor), or rifampin (moderate CYP2C8 and CYP2C9 inducer; strong CYP3A4 and CYP219 inducer). <h3>Methods</h3> 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; Group C received a single dose of ETR 2mg. From Days 8–22 (Period 2), Groups A and B received fluconazole 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; Group C received rifampin 600mg QD and a single dose of ETR 2mg on Day 15. Primary endpoints were plasma C<sub>max</sub>, AUC<sub>0-168h</sub>, and AUC<sub>0-∞</sub> 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. <h3>Results</h3> In the presence of fluconazole or gemfibrozil, there was little impact on ETR C<sub>max</sub>, but AUC<sub>0-168h</sub> and AUC<sub>0-∞</sub> were mild-to-moderately increased (<b>Table</b>). Geometric mean t<sub>1/2</sub> 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<sub>max</sub> only slightly increased while AUC<sub>0-168h</sub> and AUC<sub>0-∞</sub> moderately decreased. Geometric mean t<sub>1/2</sub> of ETR decreased by ~50% in the presence of rifampin. All treatments were generally well tolerated. All treatment-emergent adverse events (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. <h3>Conclusions</h3> The results of this study are consistent with CYP2C8, CYP2C9, and CYP3A4 being involved in ETR metabolism; no single enzyme appears to dominate ETR elimination. The involvement of multiple CYP isoforms reduces the likelihood of ETR having a clinically relevant DDI, particularly when only a single CYP isoform is strongly or moderately inhibited/induced by a coadministered drug.

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