Drug Interactions between etrasimod and lopinavir / ritonavir

MONITOR CLOSELY: Due to the risk of bradycardia and atrioventricular (AV) block, the risk of QT prolongation and torsade de pointes arrhythmia may be increased during initiation of etrasimod treatment in patients receiving drugs that prolong the QT interval. Etrasimod may cause a transient decrease in heart rate during initiation of therapy. In the randomized placebo-controlled studies in patients with ulcerative colitis UC-1 and UC-2, following an initial dose of 2 mg on day 1, the greatest mean decrease from baseline in heart rate of 7.2 bpm occurred at hour 2 (UC-2) and hour 3 (UC-1). In studies UC-2 and UC-3, bradycardia was reported on day 1 in 2.9% of patients on etrasimod compared to none in the placebo group. On Day 2, bradycardia was reported in 1 patient (0.3%) treated with etrasimod compared to none in the placebo group. Overall, subjects who experienced bradycardia were generally asymptomatic. Few subjects experienced symptoms such as dizziness, and these symptoms resolved without intervention. Initiation of etrasimod treatment has also resulted in transient AV conduction delays. In the UC-1 study, after 2 mg of etrasimod on day 1 of treatment, first- or second-degree Mobitz type I AV blocks were observed in 0.7% of etrasimod- treated subjects compared to none in the placebo group. In studies UC-2 and UC-3, Mobitz type I AV blocks were observed in 0.8% of etrasimod-treated subjects compared to none in the placebo group. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Because bradycardia and AV block are recognized risk factors for QT prolongation and torsade de pointes arrhythmia, advice from a cardiologist should be sought if treatment with etrasimod is considered in patients with significant QT prolongation (QTcF greater than 450 msec in males or 470 msec in females), patients with arrhythmias requiring treatment with Class 1a or Class III antiarrhythmic agents, or in patients on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes or drugs that slow heart rate or AV conduction. Temporary interruption of anti-arrhythmic therapy may be required prior to initiation of etrasimod, depending on the patient's resting heart rate. Some authorities state that treatment with an anti-arrhythmic agent may be initiated in patients who have been stabilized on etrasimod therapy for at least 7 consecutive days. The manufacturer's product labeling or local treatment protocols should also be consulted for additional guidance.

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 or CYP450 2C8 in patients who are known or suspected to be poor CYP450 2C9 metabolizers may increase the exposure of etrasimod. Etrasimod is primarily metabolized by the isoenzymes CYP450 3A4, 2C8, and 2C9. Pharmacokinetic studies have reported that no single enzyme system appears to dominate the elimination pathway of etrasimod. Therefore, the involvement of multiple CYP isoforms reduces the likelihood of drug-drug interactions when only a single CYP isoform is strongly or moderately inhibited by a coadministered drug. In clinical drug interaction studies, when etrasimod was administered with the dual moderate CYP450 2C9 and 3A4 inhibitor fluconazole at steady-state levels, etrasimod systemic exposure (AUC) increased by 84%. However, concomitant use with the potent CYP450 3A4 inhibitor itraconazole or the potent CYP450 2C8 inhibitor gemfibrozil increased the AUC of etrasimod by 32% and 36%, respectively. This increase was not considered by the manufacturer to be clinically significant. The effect on etrasimod systemic exposure in CYP450 2C9 intermediate metabolizers treated with less potent CYP450 2C8 or 3A4 inhibitors is not known. Increased plasma concentrations of etrasimod may increase the risk of infections, bradyarrhythmia, AV conduction delays, elevated transaminase levels, and macular edema.

MANAGEMENT: According to the manufacturer of etrasimod, concomitant use with potent or moderate inhibitors of CYP450 3A4 or 2C8 in patients who are poor CYP450 2C9 metabolizers is not recommended. Caution is recommended with coadministration of these agents in patients who are intermediate CYP450 2C9 metabolizers.