Indications
Etrasimod is approved for the treatment of moderately to severely active ulcerative colitis (UC) in adults. In the United States, it is indicated for adults, while in other regions, it may be approved for patients aged 16 years and older. This medication is particularly suitable for individuals who have demonstrated an inadequate response, loss of response, or intolerance to either conventional therapy or biological agents.
Pharmacodynamics
Etrasimod's primary mode of action involves reducing·heral blood lymphocyte counts. Clinical studies, specifically UC-1 and UC-2, have shown that lymphocyte counts decrease to approximately 50% of baseline levels within two weeks of treatment, with these reduced levels sustained throughout the treatment period. A dose-dependent reduction in blood lymphocyte counts has also been observed. Following·he discontinuation of etrasimod at a dosage of 2 mg once daily, the median time for peripheral blood lymphocytes to return to normal is 2.6 weeks, with about 90% of patients returning·hin 4.7 weeks. Additionally, etrasimod may cause a transient decrease in heart rate and atrioventricular (AV) conduction upon treatment initiation. Initial dosing·has shown a mean decrease in heart rate of 7.2 (SD 8.98) beats per minute, observed 2 to 3 hours after administration on the first day. Notably, even at twice the maximum recommended dose, etrasimod does not cause clinically significant prolong·he QTc interval. A reduction in absolute forced expiratory volume in 1 second (FEV1) was also recorded in subjects on etrasimod.
Absorption
The pharmacokinetic profile of etrasimod reveals a mean (SD) steady-state maximum plasma concentration (Cmax) of 113 (27.5) ng·he concentration-time curve at the dosing·h/mL at the recommended dosage. The Cmax and AUC of etrasimod are approximately dose-proportional from 0.7 mg to 2 mg, reaching·hin 7 days with an accumulation factor of approximately 2- to 3-fold compared to the initial dose. The median time to reach Cmax (Tmax) is approximately 4 hours, with a rang·hours following·harmacokinetic differences are observed when etrasimod is administered with a high-fat meal consisting·hrough oxidation and dehydrogenation mediated by the enzymes CYP2C8, CYP2C9, and CYP3A4, with minor involvement from CYP2C19 and CYP2J2. Conjugation occurs mainly through UGTs, with a minor role played by sulfotransferases. In plasma, unchang·he predominant circulating component.
Mechanism of Action
Etrasimod functions as a sphingosine 1-phosphate (S1P) receptor modulator with high affinity binding to the S1P receptors 1, 4, and 5 (S1P1,4,5). It exhibits minimal interaction with S1P3, displaying 25-fold less activity than the maximum concentration at the recommended dosage, and shows no activity on S1P2. By partially and reversibly impeding lymphocytes from exiting lymphoid organs, etrasimod effectively decreases lymphocyte levels in the peripheral blood. While the precise mechanism by which etrasimod achieves its therapeutic effects in ulcerative colitis remains unclear, it is suggested that the drug may reduce lymphocyte migration into intestinal tissues.
