Mechanism Of Action
Eluxadoline is a mu-opioid receptor agonist; eluxadoline is also a delta opioid receptor antagonist and a kappa opioid receptor agonist. The binding affinities (Ki) of eluxadoline for the human mu and delta opioid receptors are 1.8 nM and 430 nM, respectively. The binding affinity (Ki) of eluxadoline for the human kappa opioid receptor has not been determined; however, the Ki for guinea pig cerebellum kappa opioid receptor is 55 nM. In animals, eluxadoline interacts with opioid receptors in the gut.
At a dose 10 times the maximum recommended dose (100 mg), VIBERZI does not prolong the QT interval to any clinically relevant extent.
Following oral administration of 100 mg VIBERZI in healthy subjects, the Cmax of eluxadoline was approximately 2 to 4 ng/mL and AUC was 12 to 22 ng.h/mL. Eluxadoline has approximately linear pharmacokinetics with no accumulation upon repeated twice daily dosing. The variability of eluxadoline pharmacokinetic parameters ranges from 51% to 98%.
Absolute bioavailability of eluxadoline has not been determined. The median Tmax value was 1.5 hours (range: 1 to 8 hours) under fed conditions and 2 hours (range: 0.5 to 6 hours) under fasting conditions.
The administration of VIBERZI with a high fat meal that contained approximately 800 to 1000 total calories, with 50% of calories being derived from fat content decreased the Cmax of eluxadoline by 50% and AUC by 60%.
Plasma protein binding of eluxadoline was 81%.
The mean plasma elimination half-life of eluxadoline ranged from 3.7 hours to 6 hours.
Metabolism of eluxadoline is not clearly established [seeDRUG INTERACTIONS]. There is evidence that glucuronidation can occur to form an acyl glucuronide metabolite.
Following a single oral dose of 300 mg [14C] eluxadoline in healthy male subjects, 82.2% of the total radioactivity was recovered in feces within 336 hours and less than 1% was recovered in urine within 192 hours.
Following a single oral 100-mg dose in subjects with varying degrees of liver impairment and healthy subjects, mean eluxadoline plasma exposure was 6-fold, 4-fold, and 16-fold higher in mild, moderate, and severe hepatically impaired subjects (Child Pugh Class A, B, C), respectively, compared to the subjects with normal liver function [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, Use in Specific Populations].
In Vitro Assessment of Drug Interactions
In vitro studies indicate that eluxadoline is neither an inducer of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant systemic concentrations. Although CYP2E1 was slightly inhibited by eluxadoline (IC50 of approximately 20 micromolar [11 mcg/mL]), clinically meaningful interactions are unlikely. The in vitro studies were not adequate to establish the potential for eluxadoline to inhibit CYP3A4 in the gut [see DRUG INTERACTIONS].
In vitro studies suggest that eluxadoline is a substrate for OAT3, OATP1B1, BSEP and MRP2, but not for OCT1, OCT2, OAT1, OATP1B3, P-gp and BCRP. Based on the in vitro studies, clinically meaningful interaction via inhibition of OCT1, OCT2, OAT1, OAT3, OATP1B3, BSEP and MRP2 by eluxadoline is unlikely. However, the in vitro studies were not adequate to establish the potential for eluxadoline to inhibit P-gp in the gut.
In Vivo Assessment Of Drug Interactions
The following drug interactions were studied in healthy subjects:
Coadministration of multiple doses of 100 mg VIBERZI with multiple dose administration of an oral contraceptive (norethindrone 0.5 mg/ethinyl estradiol 0.035 mg) does not change the exposure of either drug.
Coadministration of a single dose of 100 mg VIBERZI with a single dose of 600 mg cyclosporine resulted in 4.4-fold and 6.2-fold increase in AUC and Cmax of eluxadoline, respectively, compared to administration of VIBERZI alone [see DRUG INTERACTIONS].
Coadministration of a single dose of 100 mg VIBERZI with a single dose of 500 mg probenecid resulted in a 35% and 31% increase in eluxadoline AUC and Cmax, respectively, compared to administration of VIBERZI alone. This change in eluxadoline exposures is not expected to be clinically meaningful.
Coadministration of multiple doses of 100 mg VIBERZI twice daily with a single dose 20 mg rosuvastatin resulted in an increase in the AUC (40%) and Cmax (18%) of rosuvastatin compared to administration of rosuvastatin alone. Similar results were observed with the active, major metabolite, n-desmethyl rosuvastatin [see DRUG INTERACTIONS].
The efficacy and safety of VIBERZI in IBS-D patients was established in two randomized, multi-center, multi-national, double-blind, placebo-controlled trials (Studies 1 and 2). A total of 1281 patients in Study 1 and 1145 patients in Study 2 received treatment with VIBERZI 75 mg, VIBERZI 100 mg or placebo twice daily [overall, patients had a mean age of 45 years (range 18 to 80 years with 10% at least 65 years of age or older), 66% female, 86% white, 11% black, and 27% Hispanic].
All patients met Rome III criteria for IBS-D (loose [mushy] or watery stools ≥ 25% and hard or lumpy stools < 25% of bowel movements) and were required to meet both of the following criteria:
- an average of worst abdominal pain scores in the past 24 hours of > 3.0 on a 0 to 10 scale over the week prior to randomization.
- an average daily stool consistency score (Bristol Stool Scale or BSS) of ≥ 5.5 and at least 5 days with a BSS score ≥ 5 on a 1 to 7 scale over the week prior to randomization.
Pertinent exclusion criteria included: prior pancreatitis, alcohol abuse, cholecystitis prior 6 months, sphincter of Oddi dysfunction, inflammatory bowel disease, intestinal obstruction, gastrointestinal infection or diverticulitis within prior 3 months, lipase greater than 2 xULN, ALT or AST greater than 3 xULN.
Study 1 and Study 2 included identical 26-week double-blind, placebo-controlled treatment periods. Study 1 continued double-blinded for an additional 26 weeks for long-term safety (total of 52 weeks of treatment), followed by a 2-week follow-up. Study 2 included a 4-week single-blinded, placebo-withdrawal period upon completion of the 26-week treatment period. During the double-blind treatment phase and the single-blinded placebo withdrawal phase, patients were allowed to take loperamide rescue medication for the acute treatment of uncontrolled diarrhea, but were not allowed to take any other antidiarrheal, antispasmodic agent or rifaximin for their diarrhea. Additionally, patients were allowed to take aspirin-containing medications or nonsteroidal anti-inflammatory drugs, but no narcotic or opioid containing agents.
Efficacy of VIBERZI was assessed in both trials using an overall composite responder primary endpoint. The primary endpoint was defined by the simultaneous improvement in the daily worst abdominal pain score by ≥ 30% as compared to the baseline weekly average AND a reduction in the BSS to < 5 on at least 50% of the days within a 12-week time interval. Improvement in daily worst abdominal pain in the absence of a concurrent bowel movement was also considered a response day. Results for endpoints were based on electronic daily diary entries by patients.
The proportion of composite responders over 12 weeks is shown in Table 4. In both trials, the proportion of patients who were composite responders to VIBERZI was statistically significantly higher than placebo for both doses. The proportion of patients who were composite responders to VIBERZI was similar for male and female patients in both trials.
Table 4: Efficacy Results in Randomized Clinical Trials
|Study 1||Study 2|
VIBERZI 100mg twice daily
VIBERZI 75mg twice daily
VIBERZI 100mg twice daily
VIBERZI 75mg twice daily
|Composite1 Response over 12 weeks|
|Treatment difference 95% CI (%)||8%2 (2.6, 13.5)||7%4 (1.4, 12.2)||13%3 (7.5, 19.2)||13%3 (6.8, 18.5)|
|Composite Response over 26 weeks|
|Treatment difference 95% CI (%)||10% (4.7, 16.1)||4% (-1.0, 9.9)||13% (6.4, 18.8)||10% (4.2, 16.4)|
|Abdominal Pain Response Improved ≥ 30% over 12 weeks|
|Treatment difference 95% CI (%)||4% (-3.0, 10.2)||3% (-3.8, 9.4)||6% (-1.3, 12.8)||3% (-4.3, 9.8)|
|BSS < 5 Response over 12 weeks|
|Treatment difference 95% CI (%)||12% (6.3, 18.2)||8% (2.1, 13.8)||15% (8.4, 21.0)||16% (9.7, 22.4)|
1Composite= Simultaneous improvement of Worst Abdominal Pain (WAP) by ≥ 30% and Bristol Stool Score (BSS) < 5 on the same day for ≥ 50% of days over the interval
2 P < 0.01
3 P < 0.001
4 P < 0.05
Additionally, the proportion of patients who were composite responders to VIBERZI at each 4week interval was numerically higher than placebo for both doses as early as month 1 through month 6 demonstrating that efficacy is maintained throughout the course of treatment.
During the 4 week single-blind withdrawal period in Study 2, no evidence of worsening of diarrhea or abdominal pain compared to baseline was demonstrated at either dose.
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