Chemical formula: C₂₆H₂₆F₃NO₃ Molecular mass: 457.186 g/mol PubChem compound: 44623998
Etrasimod is a sphingosine-1-phosphate (S1P) receptor modulator that binds to S1P receptors 1, 4 and 5 (S1P1,4,5) and is a balanced G-protein and beta-arrestin agonist at S1P1. Etrasimod has minimal activity on S1P3 and no activity on S1P2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood thereby lowering the number of activated lymphocytes in the tissue.
The mechanism by which etrasimod exerts therapeutic effects in ulcerative colitis (UC) is unknown but may involve the reduction of lymphocyte migration into sites of inflammation. The etrasimod-induced reduction of lymphocytes in the peripheral circulation has differential effects on leucocyte subpopulations, with greater decreases in cells involved in the adaptive immune response known to be involved in driving UC pathology. Etrasimod has minimal impact on cells involved in innate immune response, which contribute to immunosurveillance.
Etrasimod may result in a transient decrease in heart rate and AV conduction upon treatment initiation. On Day 1, in UC patients from ELEVATE UC 52 and ELEVATE UC 12, 33% of subjects had bradycardia (nadir HR below 60 bpm within the first 4 hours), or significant bradycardia in 2.5% (HR nadir below 50 bpm). No patients had HR <40 bpm following the first dose. The greatest mean decrease in heart rate was observed at Hour 2 or 3 post dose. On Day 1, the mean (SD) change in PR interval from predose to 4 hours post dose with etrasimod was 5.5 msec (18.84). PR interval prolongation >200 msec was recorded on ECG in 5.1% and higher degree prolongation (>230 msec) in 1.8% of subjects.
In controlled clinical studies, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 × 109/L) consistent with the mechanism of action, and lowered lymphocyte counts were maintained during once daily treatment with etrasimod. A reduction in neutrophil counts was observed in controlled clinical studies with etrasimod, mean neutrophil counts were generally in the normal range during etrasimod treatment. Lowered neutrophil counts were maintained on etrasimod treatment and were reversible upon treatment discontinuation.
Peripheral blood B cells [CD19+] and T cells [CD3+], T-helper [CD3+CD4+], and T-cytotoxic [CD3+CD8+] cell subsets were all reduced, while natural killer cells and monocytes were not. T-helper cells were more sensitive to the effects of etrasimod than T-cytotoxic cells.
Peripheral blood absolute lymphocyte counts returned to the normal range in 90% of patients within 1 to 2 weeks of stopping therapy based on a population pharmacokinetic/pharmacodynamic model.
Following etrasimod single oral dosing, Cmax and AUC increased approximately dose-proportionally in the dose-range studied (0.1 mg to 5 mg). Following multiple dosing, mean Cmax and AUC increased slightly more than dose proportional from 0.7 mg to 2 mg. Steady state plasma concentrations are reached within 7 days following 2 mg once daily dosing, with a mean Cmax of 113 ng/mL and AUCtau of 2163 h*ng/mL. Estimated steady state etrasimod accumulation ratio ranges from about 2- to 3–fold. The pharmacokinetics of etrasimod is similar in healthy subjects and subjects with UC.
The time (Tmax) to reach maximum plasma concentrations (Cmax) after oral administration of immediate release oral pharmaceutical forms of etrasimod is approximately 4 hours (range 2–8 hours). Etrasimod absorption is extensive, based on high permeability and observation of relatively little intact etrasimod eliminated in the faeces (11.2% of administered radioactive dose).
Food intake can result in slightly delayed absorption (the median Tmax increased by 2 hours). Food does not have an effect on etrasimod exposure measures (Cmax and AUC); therefore, etrasimod can be administered without regard to meals.
Etrasimod distributes to body tissues with a mean oral volume of distribution (Vz/F) of 66 L. Etrasimod is highly bound to human plasma proteins (97.9%), primarily albumin and mainly distributed in the plasma fraction of whole blood with blood-to-plasma ratio of 0.7.
Etrasimod is extensively metabolised via CYP2C8 (38%), CYP2C9 (37%), and CYP3A4 (22%), and with minor contributions via CYP2C19 and CYP2J2. The major circulating component in plasma is unchanged etrasimod and main metabolites M3 and M6. Etrasimod contributes to the majority of S1P pharmacology (>90%). Etrasimod is extensively metabolised by oxidation, dehydrogenation, and conjugation by UGTs and sulfotransferases.
Etrasimod is not a substrate of P-gp, BCRP, OATP1B1/3, OAT1/3, or OCT1/2 transporters. Medicinal products that are inhibitors of these transporters are unlikely to impact the pharmacokinetics of etrasimod.
After oral administration, the apparent steady state oral clearance (CL/F) was approximately 1 L/h. The mean plasma effective elimination half-life (t1/2) of etrasimod is approximately 30 hours.
Etrasimod is primarily eliminated hepatically with 82% recovery of a total radioactive dose in the faeces and 4.89% in the urine. Unchanged etrasimod was only detected in faeces, but not in urine.
In vitro studies indicate that, at the recommended dose of 2 mg once daily, etrasimod is unlikely to show any clinically relevant interaction potential for CYP or membrane transporters.
No dose adjustments are needed in patients with renal impairment as Cmax and AUC were comparable between subjects with severe renal impairment and subjects with normal renal function. The severe renal impairment cohort included 2 subjects with eGFR ≤29 mL/min (not on haemodialysis), and 6 subjects with ESRD who received haemodialysis prior to administration of etrasimod. The impact of haemodialysis performed after etrasimod administration has not been evaluated.
Etrasimod is contraindicated in patients with severe hepatic impairment. No dose adjustments are needed in patients with mild or moderate hepatic impairment. The total etrasimod AUC parameters are 13%, 29%, and 57% higher in subjects with mild, moderate, and severe hepatic impairment, respectively, compared with subjects with normal liver function for the 2 mg single dose studied.
Population pharmacokinetic analyses showed that age did not have an effect on the pharmacokinetics of etrasimod in patients over 65 years of age (n=40 (3.7%) of patients were aged ≥65). There is no meaningful difference in the pharmacokinetics in elderly patients compared to younger patients.
The systemic exposure of etrasimod 2 mg is not altered by body weight differences to a clinically meaningful extent in patients with body weight ≥40 kg. In patients with body weight below 40 kg, an approximately 1.5-fold increase in exposure is predicted.
Population pharmacokinetics analysis showed that sex, race, or ethnicity has no clinicially significant effect on etrasimod pharmacokinetics.
A population pharmacokinetics analysis predicted similar etrasimod exposures in adult and older adolescent (16 to <18 years old) patients with UC.
No data are available on administration of etrasimod to paediatric or adolescent patients below the age of 16 years.
Nonclinical data reveal no special hazard for etrasimod in humans with the following exception: changes in the left ventricular arteries (hypertrophy/hyperplasia of the tunica media) were observed in 3- and 9- month repeat-dose toxicity studies in dogs at exposures ≥ 24 times the recommended human dose (RHD) exposure based on AUC. The relevance of this finding for humans is uncertain. Furthermore, the exposure to the most abundant human metabolites (M3 and M6) was investigated in rats only. The relevance for humans is uncertain.
Etrasimod did not affect male and female fertility in rats up to the highest dose tested, representing an approximate 467-fold exposure margin based on human systemic exposures at the RHD for males and 21-fold for females.
Etrasimod administration to pregnant rats and rabbits daily during organogenesis resulted in post-implantation loss with a corresponding lower number of viable foetuses and foetal external, visceral, and/or skeletal malformations and variations in the absence of maternal toxicity. Malformations were observed at the lowest dose tested in rats with maternal plasma AUC approximately 5 times that in humans at the RHD. The exposure at the no-adverse-effect dose (2 mg/kg/day) in the rabbit was approximately 0.8 times, that in humans at the RHD of 2 mg/day.
Following daily oral administration of etrasimod through pregnancy and lactation in rats, decreased mean pup weights, lower pup viability, and reduced fertility and reproductive performance (reduction in implantations and increased preimplantation loss) in F1 pups were observed. Plasma exposure (AUC) in dams at the lowest dose tested was equivalent (1.1 times) to those in humans at the RHD. Etrasimod was detected in the plasma of F1 pups, indicating exposure from the milk of the lactating dam.
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