Abstract
Eluxadoline is approved for the treatment of diarrhea‐predominant irritable bowel syndrome in the United States. The impact of renal impairment on the pharmacokinetic (PK) parameters of eluxadoline is currently unknown. This phase 1, open‐label, parallel‐group study evaluated the PK and safety profile of eluxadoline in 8 participants with renal impairment and 8 matched healthy controls. Of the participants with renal impairment, 2 had severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and 6 had end‐stage renal disease while not yet on dialysis (eGFR <15 mL/min/1.73 m2). The primary objective was to assess plasma and urine PKs, and plasma protein binding of eluxadoline. In participants with renal impairment, mean plasma concentrations of eluxadoline were consistently higher compared with matched healthy controls: 1.4‐fold higher for mean maximum plasma concentration (Cmax) and 2.2‐fold higher for mean area under the plasma concentration‐time curve from time 0 to time t. The median time to Cmax was 2.5 hours in both groups. Although eluxadoline is a locally acting drug with low oral bioavailability, because of the increased systemic exposure in participants with renal impairment as a cautionary measure the lower approved dose of 75 mg twice daily is recommended for individuals with severe renal impairment and end‐stage renal disease while not yet on dialysis. Eluxadoline 100 mg single dose was well tolerated in participants with renal impairment and matched healthy controls.
Keywords: irritable bowel syndrome with diarrhea (IBS‐D), eluxadoline, pharmacokinetics, renal impairment, end‐stage renal disease (ESRD)
Approximately 15% of the adult population in the United States are estimated to have chronic kidney disease, but as many as 9 in 10 adults with the condition do not know they have it. 1 By 2016, nearly 700 000 people in the United States were living with end‐stage renal disease (ESRD). 2 Patients with kidney disease are susceptible to variations in drug exposure 3 ; when treated at the same dose, circulating drug concentrations can differ between individuals with renal impairment and those with normal kidney function. 4 It is therefore widely acknowledged that drugs cleared by the kidney require dose adjustment in both acute and chronic conditions. 5 However, impaired renal function has also been associated with changes in the hepatic clearance, intestinal absorption and first‐pass metabolism, hepatic, renal, and intestinal transport, plasma protein binding, and/or tissue distribution of a drug, which can have implications for drug absorption. 5 As some reports have indicated that impaired renal function can alter some drug metabolism and transport pathways in the liver and gut, 5 , 6 , 7 even drugs that are eliminated by nonrenal transport and metabolism could require dose adjustment in patients with reduced renal function. 5 A study investigating elimination‐pathway dependency in the effect of chronic kidney disease on several nonrenal clearance pathways reported a decrease in the clearance of multiple cytochrome P450 (CYP)2C8 and organic anion‐transporting polypeptide model drug substrates with increasing severity of chronic kidney disease. 8 Moreover, published studies on the clearance of benzodiazepine derivatives in patients with renal insufficiency did not show a lower total clearance of the target drug compared to controls, although free clearance in patients with renal impairment was significantly lower than controls in 2 of the 9 reviewed studies (after normalization for differences in free fraction). 9
Eluxadoline is a mixed μ‐opioid and κ‐opioid receptor agonist and δ‐opioid receptor antagonist approved for the treatment of diarrhea‐predominant irritable bowel syndrome (IBS‐D). 10 , 11 Following oral administration, eluxadoline is poorly absorbed, with an estimated systemic availability of approximately 1%. 12 It has gastrointestinal transit‐inhibiting activity, 13 and the safety and effectiveness of eluxadoline to treat the symptoms of IBS‐D have been demonstrated in 2 large, randomized, phase 3 clinical studies. 14 , 15 , 16 Eluxadoline is generally well tolerated, with incidences of nausea, constipation, and abdominal pain being the most common adverse events. 14 , 16 , 17 Pancreatitis was the most commonly reported serious adverse event; however, the overall incidence was low (0.4%). 16
A human mass balance study found that following administration of a single dose of radiolabeled eluxadoline 300 mg, an average of 0.1% of the administered dose was recovered in the urine after 192 hours, and 82% of the administered dose was recovered in feces after 336 hours, 18 thus renal clearance plays a minor role in eluxadoline excretion. Of note, some studies have found that renal insufficiency reduces even nonrenal clearance. 9 Although the mechanisms through which renal impairment affects the pharmacokinetics (PK) of nonrenally eliminated drugs are not well understood, proposed factors include direct alterations in hepatic enzyme efficiency or indirect effects via changes to drug absorption, protein binding, hepatic uptake, or accumulation of metabolites. 8 , 19
While the kidneys play a minor role in the elimination of eluxadoline, the extent to which renal impairment might impact the drug's PK parameters is currently unknown. This study was conducted to compare the PK, safety, and tolerability profiles of a single oral dose of eluxadoline in participants with severe renal impairment or ESRD not yet on dialysis relative to matched, healthy participants with normal renal function.
Methods
Participant Population
This phase 1, single‐dose, open‐label, parallel‐group study was conducted from April 2016 to February 2018 at three centers in the United States, the full details of which are given in Table S1.
This study enrolled 16 participants (male or female) aged between 18 and 80 years with body mass index ≥18 and ≤42 kg/m2. 8 participants had renal impairment and the remaining 8 healthy participants had normal renal function, with each healthy participant matched to the age, gender, and weight of the participants with renal impairment (difference of ±5 years for age and ±10% for weight). Renal function was determined using an estimated glomerular filtration rate (eGFR) from the Modification of Diet in Renal Disease equation, as defined by the National Kidney Foundation. 20 Of the 8 participants with renal impairment, 2 had severe renal impairment and 6 had ESRD and were not yet on dialysis. The study enrolled the 2 participants with severe renal impairment based on the original protocol, in which participants with severe renal impairment (defined as eGFR 15–29 mL/min/1.73 m2) were to be enrolled. After enrolling these 2 participants, the protocol was amended, per guidance from the US Food and Drug Administration to the sponsor, such that participants with ESRD not yet on dialysis (defined as eGFR <15 mL/min/1.73 m2) would be enrolled. Normal renal function was defined as eGFR ≥90 mL/min/1.73 m2.
Participants were assessed based on medical history, physical examination, and laboratory and other test results consistent with their degree of renal impairment, as determined by the investigator. For healthy participants, state of general good health was based on medical history and routine physical examination. Full inclusion and exclusion criteria are listed in Table S2.
Study Design
An overview of the study design is shown in Figure 1. Following a 14‐day screening period (days −14 to −1), the dosing period ran from days −1 to 4, during which time participants were housed overnight at a study center. Prior to dose administration on day 1, participants fasted for 10 hours overnight and consumed a standardized breakfast in the morning. The study drug was administered with food, per the prescribing information. Thirty minutes following the start of breakfast, participants received a single dose of eluxadoline 100 mg with 240 mL of water. Following dose administration, participants fasted and remained seated upright and awake for 4 hours, during which time they received 120 mL of water every hour to promote urine production. Participants were released from the study center on day 4 and an end‐of‐study visit was conducted on or within 7 days of day 4. The maximum anticipated duration of study participation was 12 days (days −1 to 11).
Figure 1.
Study design. aThe screening period ran from day −14 to day −1. bThe dosing period ran from day −1 to day 4, during which participants were housed overnight at a study center on days −1 to 3, prior to release on day 4. cAn end‐of‐study visit was conducted on or within 7 days of day 4.
A single dose of eluxadoline 100 mg was chosen for this study to match the highest recommended dose given in a single setting. With a terminal half‐life ranging from 3.7 to 6 hours, 18 eluxadoline is not expected to exhibit accumulation on repeated twice‐daily dosing. As the renal route is a minor elimination pathway, a notable increase in exposure was not anticipated in participants with ESRD not yet on dialysis.
This study was conducted in accordance with the International Council for Harmonisation E6 guideline for good clinical practice and the principles of the Declaration of Helsinki. The institutional review board (IntegReview IRB) approved the study protocol prior to study initiation (the full details of which are given in Table S1) and written informed consent was obtained from all participants at the first study visit.
Study Objectives and Assessments
The study's primary objective was to assess the PKs, safety, and tolerability profile of a single oral dose of eluxadoline in participants with severe renal impairment or ESRD not yet on dialysis compared with matched, healthy participants with normal renal function.
Study assessments included evaluation of eluxadoline PKs in plasma and urine, plasma protein binding of eluxadoline, and safety. Sample collection for evaluation of PKs in plasma occurred at 0 hours predose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours postdose, cumulative urine collection for evaluation of PK in urine occurred at −2 to 0 hours predose, and at 0–4, 4–8, 8–12, 12–24, 24–48, and 48–72‐hour intervals postdose, and sample collection for evaluation of plasma protein binding occurred at 0 hours predose and 2 hours postdose.
Safety assessments included evaluation of treatment‐emergent adverse events (TEAEs; coded using the Medical Dictionary for Regulatory Activities [MedDRA] version 20.1), vital signs, electrocardiograms (ECGs), physical examinations, and clinical laboratory assessments. Adverse events (AEs) were assessed throughout the study from completion of the informed consent form until 30 days after administration of the dose of eluxadoline. The severity of each AE and its causality in relation to the study drug was assessed by the investigators. An AE occurring during the treatment period was considered a TEAE if it was not present before the administration of eluxadoline or if it was present before dosing but increased in severity during the treatment period.
Clinical laboratory tests were carried out by the local laboratory affiliated with each study center. Eluxadoline concentrations in plasma/urine samples were analyzed using validated liquid chromatography with tandem mass spectrometry detection methods; the lower limit of quantification was 0.1 ng/mL in plasma, 1.00 ng/mL in urine, and 5.00 pg/mL for plasma protein binding (see Supporting Information, Measurements for further details).
Statistical Analyses
The 2 analysis populations were the PK population, consisting of all participants who had evaluable PK parameters, and the safety population, consisting of all participants who received the eluxadoline dose.
Baseline characteristics, exposure to eluxadoline, and concomitant medication use were summarized for the safety population using descriptive statistics. Participants with severe renal impairment and participants with ESRD not yet on dialysis were combined. Medical/surgical history was coded using MedDRA version 20.1.
Prior medications were defined as any hormonal product taken within 30 days or any other medication taken within 14 days prior to eluxadoline administration. A concomitant medication was defined as any medication taken during the study between eluxadoline administration and the end‐of‐study visit.
The principal PK parameters were analyzed using noncompartmental methods using Phoenix WinNonlin™ version 8.0 (Certara, Princeton, New Jersey) and included:
maximum plasma drug concentration (Cmax)
time of maximum drug concentration (Tmax)
area under the plasma concentration–time curve from time 0 to time t (AUC0–t).
Urine measurements were the cumulative amount of unchanged drug excreted into the urine from time 0 to time t (Ae0–t), the percentage of the dose excreted as unchanged drug in urine (%Dose), and the renal clearance of drug from plasma (CLR).
For all PK parameters, descriptive statistics were provided by participant group for all participants in the PK population. Statistical comparisons of PK parameters included the comparison of participants with ESRD not yet on dialysis (n = 6) versus their matched, healthy participants with normal renal function (n = 6), and all participants with renal impairment (ESRD not yet on dialysis + severe renal impairment, n = 8) versus all matched, healthy participants with normal renal function (n = 8). While 3 outliers for PK parameters (healthy controls, n = 1; participants with ESRD not yet on dialysis, n = 2) were identified utilizing the Turkey method, 21 all participants were included for all PK and safety analyses, thus both arithmetic and geometric mean values are presented, given the large intersubject variability due to low oral bioavailability.
Safety results, including AEs, clinical laboratory parameters, vital signs, and ECG parameters, were summarized using descriptive statistics or listed for each participant as appropriate. The last assessment made before the administration of eluxadoline was used as the baseline for all analyses of that parameter and no formal statistical analyses were performed. The descriptive statistics for clinical laboratory parameters, vital signs, ECGs at baseline, and change from baseline to the end of the study, were presented by the participant group; the number of participants who had potentially clinically significant postbaseline values was also assessed by the participant group. For vital signs and ECGs, mean changes from baseline to PK profiling times were also assessed.
Results
Participant Disposition and Demographics
A total of 16 participants were enrolled and completed the study: 8 with renal impairment (2 with severe renal impairment and 6 with ESRD not yet on dialysis) and 8 healthy participants with normal renal function. All participants received a single dose of eluxadoline 100 mg on day 1.
Given that participants with normal renal function were matched by age, gender, and weight to the participants with renal impairment (difference of ±5 years for age and ±10% for weight), the demographic data were similar between these 2 groups (Table 1). In both groups, 75% of participants were male and the mean age was approximately 61 years. Participants with normal renal function had a mean eGFR of 110.3 mL/min/1.73 m2 (range 95–131), while the mean eGFR for participants with renal impairment was 13.8 mL/min/1.73 m2 (range 8–28), as calculated using the Modification of Diet in Renal Disease equation. Within the group with renal impairment, the 2 participants with severe renal impairment had eGFR 28 and 18 mL/min/1.73 m2, while the remaining 6 participants with ESRD not yet on dialysis had eGFR values ranging from 8 to 14.7 mL/min/1.73 m2.
Table 1.
Demographics and Baseline Characteristics According to Renal Function (Safety Population)
| Renal Impairment b | |||||
|---|---|---|---|---|---|
| Normal Renal Function a (N = 8) | ESRD + Severe (N = 8) | ESRD (N = 6) | Severe (N = 2) | All Participants (N = 16) | |
| Age (years), mean (SD) | 60.9 (9.2) | 61.3 (8.3) | 57.8 (5.3) | 71.5 (7.8) | 61.1 (8.4) |
| Male, n (%) | 6 (75.0) | 6 (75.0) | 4 (66.7) | 2 (100.0) | 12 (75.0) |
| Race, n (%) | |||||
| White | 5 (62.5) | 4 (50.0) | 3 (50.0) | 1 (50.0) | 9 (56.3) |
| Black or African American | 3 (37.5) | 4 (50.0) | 3 (50.0) | 1 (50.0) | 7 (43.8) |
| Hispanic or Latino, n (%) | 5 (62.5) | 6 (75.0) | 4 (66.7) | 2 (100.0) | 11 (68.8) |
| Weight (kg) mean (SD) | 83.1 (12.1) | 81.7 (9.6) | 80.3 (10.9) | 85.8 (2.5) | 82.4 (10.6) |
| BMI (kg/m2) mean (SD) | 29.0 (5.0) | 30.8 (4.8) | 31.0 (5.6) | 30.3 (1.6) | 29.9 (4.8) |
| eGFR (mL/min/1.73 m2), mean (SD) | 110.3 (11.2) | 13.8 (6.7) | 10.8 (2.8) | 23.0 (7.1) | 62.0 (50.6) |
Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; ESRD, end‐stage renal disease; SD, standard deviation.
eGFR ≥ 90 mL/min/1.73 m2.
beGFR < 30 mL/min/1.73 m2 for participants with severe renal impairment and eGFR < 15 mL/min/1.73 m2 for participants with ESRD not yet on dialysis.
All 8 (100%) of the participants with renal impairment and 5 (62.5%) of the participants with normal renal function had a history of 1 or more health‐related conditions and/or surgeries at screening (see Supporting Information, Demographics and Other Baseline Characteristics and Medical/Surgical History and Physical Examinations Findings at Screening for further details). At screening, all 8 (100%) of the participants with renal impairment had prior and/or ongoing medication use, but none of the participants with normal renal function were reported to have prior or ongoing medications (see Supporting Information, Demographics and Other Baseline Characteristics, Prior and concomitant medications and Table S3 for further details).
Pharmacokinetics
Eluxadoline protein binding was generally comparable between participants with renal impairment (ESRD not yet on dialysis + severe renal impairment, n = 8) and their healthy, matched controls (76.4% vs 78.4%, respectively), and between participants with ESRD not yet on dialysis and their healthy, matched controls (77.1% vs 77.5%, respectively), thus the PK analyses were conducted based on total concentrations (Table 2).
Table 2.
Geometric and Arithmetic Means (%CV) for the PK Parameters of Eluxadoline Following a Single Oral Dose of 100 mg
| Participants With ESRD Not Yet on Dialysis and Matched, Healthy Participants With Normal Renal Function | Participants With Renal Impairment (ESRD Not Yet on Dialysis + Severe Renal Impairment) and Matched, Healthy Participants With Normal Renal Function | |||||
|---|---|---|---|---|---|---|
| PK Parameter | ESRD (N = 6) |
Normal (N = 6) |
% Geometric Mean Ratio (90%CI) [N = 6 Each] |
ESRD + Severe (N = 8) |
Normal (N = 8) |
% Geometric Mean Ratio (90%CI) [N = 8 each] |
| Cmax (ng/mL) | ||||||
| Arithmetic (%CV) | 2.9 (88.8) | 1.2 (108.6) |
222.3 (90.1–546.4) |
3.3 (69.8) | 4.2 (145.5) |
141.5 (50.9–393.1) |
| Geometric (%CV) | 2.0 (124.9) | 0.91 (84.4) | 2.5 (111.9) | 1.8 (236.1) | ||
| Tmax (h), median (min–max) | 2.5 (2.0–3.0) | 1.8 (0.5–8.0) | – | 2.5 (2.0–4.0) | 2.5 (0.5–8.0) | – |
| AUC0–t (ng/h/mL) | ||||||
| Arithmetic (%CV) | 31.2 (110.2) | 5.3 (67.6) |
417.9 (153.7–1136.4) |
29.6 (98.9) | 24.0 (158.2) |
221.4 (74.7–656.8) |
| Geometric (%CV) | 18.9 (185.4) | 4.5 (63.4) | 20.2 (139.5) | 9.1 (248.2) | ||
| Ae0–t (mg) | ||||||
| Arithmetic (%CV) | 0.02 (122.9) | 0.05 (38.3) | – | 0.03 (114.7) | 0.22 (164.2) | – |
| Geometric (%CV) | 0.008 (188.4) | 0.05 (42.1) | 0.01 (243.5) | 0.09 (207.9) | ||
| CLR (mL/min) | ||||||
| Arithmetic (%CV) | 8.5 (63.4) | 181.7 (28.0) | – | 16.4 (108.7) | 173.3 (26.9) | – |
| Geometric (%CV) | 7.1 (76.8) | 174.2 (35.0) | 10.7 (126.5) | 167.0 (31.1) | ||
| Plasma protein binding at 2 h postdose (%) | ||||||
| Arithmetic (%CV) | 77.2 (3.3) | 77.50 (3.9) | – | 76.40 (3.7) | 78.43 (3.9) | – |
| Geometric (%CV) | 77.1 (3.3) | 77.45 (3.9) | 76.36 (3.7) | 78.38 (4.0) | ||
Abbreviations: %CV, coefficient of variation; Ae0–t, cumulative amount of unchanged drug excreted into the urine from time 0 to time t; AUC0–t, area under the plasma concentration–time curve from time 0 to time t; CI, confidence interval; CLR, renal clearance of drug from plasma; Cmax, maximum plasma drug concentration; ESRD, end‐stage renal disease; PK, pharmacokinetic; Tmax, time of maximum drug concentration.
The mean plasma concentration of eluxadoline after a single, 100 mg oral dose was consistently higher in participants with renal impairment (ESRD not yet on dialysis + severe renal impairment, n = 8) than in participants with normal renal function (n = 8) (Figure 2).
Figure 2.
Mean plasma concentrations of eluxadoline after oral administration of eluxadoline 100 mg. Mean plasma concentration (ng/mL) shown on a semi‐logarithmic scale for participants with renal impairment (ESRD not yet on dialysis + severe renal impairment, n = 8) and their matched, healthy participants with normal renal function (n = 8). Bars show standard error. ESRD, end‐stage renal disease.
After a single oral dose of eluxadoline 100 mg, participants with renal impairment (ESRD not yet on dialysis + severe renal impairment, n = 8) exhibited a 1.4‐fold higher Cmax (geometric mean) and a 2.2‐fold higher AUC0–t (geometric mean) compared with matched, healthy participants with normal renal function (Table 2). The median Tmax of eluxadoline was 2.5 hours in both groups. In participants with ESRD not yet on dialysis, geometric mean Cmax was 2.2‐fold higher and geometric mean AUC0–t was 4.2‐fold higher versus matched, healthy participants with normal renal function (n = 6 each). The median Tmax of eluxadoline was 2.5 hours in participants with ESRD not yet on dialysis compared with 1.75 hours in matched, healthy participants with normal renal function.
Recovery of eluxadoline in urine was higher in participants with normal renal function than in those with renal impairment (ESRD not yet on dialysis + severe renal impairment, n = 8), a geometric mean of 0.09% and 0.01% of the dose, respectively. Similarly, geometric mean renal clearance of eluxadoline was higher in participants with normal renal function (167.0 mL/min) than in those with renal impairment (10.7 mL/min).
Similar results were observed when examining eluxadoline recovery in urine for the subgroup of participants with ESRD not yet on dialysis and their matched, healthy participants with normal renal function (n = 6 each): a geometric mean of 0.008% and 0.05% of the eluxadoline dose, respectively, was recovered in urine. In participants with ESRD not yet on dialysis, geometric mean renal clearance was 7.1 mL/min compared with 174.2 mL/min in matched, healthy participants.
Safety
Six of the 16 participants (37.5%) had one or more TEAE(s) following administration of eluxadoline 100 mg, 3 of 8 participants in each group (Table 3). Overall, the most common TEAE was abdominal discomfort (n = 3, 18.8%). Among those with normal renal function, TEAEs included 1 report each (12.5%) of abdominal discomfort, constipation, and headache, while among those with renal impairment, TEAEs included 2 reports (25.0%) of abdominal discomfort and 1 each (12.5%) of somnolence, hot flush, and upper respiratory tract infection (Table 3). Within the renal impairment group, the participant who reported the upper respiratory tract infection had ESRD not yet on dialysis; the other TEAEs that occurred within this group were reported by participants with severe renal impairment. All TEAEs were evaluated as mild and all except for the upper respiratory tract infection were related to eluxadoline.
Table 3.
Treatment‐Emergent Adverse Events (Safety Population)
| Normal Renal Function (N = 8) n (%) | Renal Impairment (N = 8) n (%) | All Participants (N = 16) n (%) | |
|---|---|---|---|
| Participants with at least one TEAE | 3 (37.5) | 3 (37.5) | 6 (37.5) |
| Gastrointestinal disorders | 2 (25.0) a | 2 (25.0) a | 4 (25.0) a |
| Abdominal discomfort | 1 (12.5) a | 2 (25.0) a | 3 (18.8) a |
| Constipation | 1 (12.5) a | 0 | 1 (6.3) a |
| Infections and infestations | 0 | 1 (12.5) b | 1 (6.3) b |
| URTI | 0 | 1 (12.5) b | 1 (6.3) b |
| Nervous system disorders | 1 (12.5) a | 1 (12.5) a | 2 (12.5) a |
| Headache | 1 (12.5) a | 0 | 1 (6.3) a |
| Somnolence | 0 | 1 (12.5) a | 1 (6.3) a |
| Vascular disorders | 0 | 1 (12.5) a | 1 (6.3) a |
| Hot flush | 0 | 1 (12.5) a | 1 (6.3) a |
Abbreviations: TEAE, treatment‐emergent adverse event; URTI, upper respiratory tract infection.
Note: The total row includes all participants who had one or more TEAEs. Participants who had more than one TEAE in different system organ classes are counted only once in the overall total. Similarly, participants who had more than one TEAE by preferred term within a system organ class are counted only once in the total for that system organ class.
Resolved during the study period, evaluated as mild and related to eluxadoline.
Resolved during the study period, evaluated as mild and not related to eluxadoline.
All TEAEs evaluated as related to eluxadoline resolved quickly; one occurred on day 2 (constipation) and resolved the following day, and the remainder (3 participants with abdominal discomfort and 1 participant each with hot flush, somnolence, or headache) occurred on the day of eluxadoline administration and resolved that same day. Prune juice was given to the participant with constipation, but no other treatment was administered for TEAEs and no participant reported the same TEAE more than once during the study.
There were no serious AEs (including deaths), TEAEs that resulted in discontinuation from the study, or TEAEs that were otherwise evaluated as significant. There was no apparent adverse trend in the incidence of TEAEs among those with renal impairment relative to those with normal renal function or among those with ESRD not yet on dialysis relative to those with severe renal impairment. Importantly, this also applied to central nervous system events, with only 1 report each of somnolence in a participant with severe renal impairment and headache in a participant with normal renal function (Table 3).
There were no abnormal laboratory values (including those that met Hy's law criteria), vital sign measurements, or 12‐lead ECG results reported as a TEAE, including values associated with renal impairment (blood urea nitrogen and creatinine). Few participants had potentially clinically significant postbaseline laboratory test results; most of those who did were within the renal impairment group, and of these, all were participants with ESRD not yet on dialysis.
Discussion
This phase 1, open‐label study evaluated the PK, safety, and tolerability of a single oral dose of eluxadoline 100 mg in matched participants with and without renal impairment. In ESRD participants not yet on dialysis, Cmax and AUC0–t of eluxadoline increased 2.2‐ and 4.2‐fold, respectively, compared with matched, healthy participants with normal renal function. In participants with renal impairment (ESRD not yet on dialysis + severe renal impairment, n = 8), Cmax and AUC0–t of eluxadoline increased 1.4‐ and 2.2‐fold, respectively, compared with matched, healthy participants with normal renal function.
Compared with healthy participants in a previous study who received 100 mg of eluxadoline, similar levels of eluxadoline exposure were observed for participants with ESRD in this study (Cmax 2.4 ng/mL and AUC0–t 17.3 ng/h/mL [n = 59] vs Cmax 2.0 ng/mL and AUC0–t 18.9 ng/h/mL [n = 6], respectively). 22 A supratherapeutic dose (eluxadoline 1000 mg) was found to be safe and well tolerated in these same healthy participants, thus 2.2‐ and 4.2‐fold increases in Cmax and AUC0–t, respectively, may not pose safety issues. Nonetheless, prolonged exposure to eluxadoline may lead to accumulation and adversely impact patients with renal insufficiencies.
Previous clinical studies in healthy participants found that a single 100 mg oral dose of eluxadoline post a 10‐hour fast was poorly absorbed, with the drug being excreted primarily through the feces and with no identifiable metabolites in the urine. 18 While the recovery of eluxadoline in urine in this study was higher in participants with normal renal function than in those with renal impairment (0.09% vs 0.01%, respectively), the mean plasma protein binding of eluxadoline was similar between the 2 groups (78.4% and 76.4%, respectively). The urinary excretion data from this study confirmed results observed in the human mass balance study (EDI1003), in which 0.2% of eluxadoline 300 mg was excreted in the urine, confirming that the renal route is a minor elimination pathway of eluxadoline (data on file).
Overall, the safety profile observed in this study following a single dose of eluxadoline 100 mg in participants with renal impairment was consistent with the known safety profile of eluxadoline. 14 No new or unexpected adverse safety signals were identified and the degree of renal impairment did not appear to impact TEAEs, all of which were mild in intensity. In addition, there were no apparent adverse findings in clinical laboratory test results, vital signs, or ECG results on review of mean changes from baseline and potentially clinically significant postbaseline test results.
Although eluxadoline is a locally acting drug with low oral bioavailability, given the increase in systemic exposure in renally impaired patients, a lower approved dose of 75 mg twice daily for individuals with severe renal impairment (eGFR < 30 mL/min/1.73 m2) and those with ESRD not yet on dialysis (eGFR < 15 mL/min/1.73 m2) is recommended as a precautionary measure to reduce potential accumulation on prolonged dosing and to reduce the risk of experiencing adverse drug events. 14 , 16
A limitation of this study is the use of a small participant population (n = 16) that was predominantly male (n = 12). This may not accurately capture exposure in the larger population of patients receiving eluxadoline treatment, especially as both chronic kidney disease 23 and IBS‐D 24 are more common in women. In addition, this study assessed administration of a single dose of eluxadoline, but the effects of impaired renal function over prolonged exposure may differ.
Conclusions
The results of this study suggest that ESRD or severe renal impairment impacts the systemic exposure of eluxadoline. The lower approved dose of eluxadoline 75 mg twice daily is recommended for patients with severe renal impairment or ESRD not yet on dialysis. Eluxadoline 100 mg single dose was safe and well tolerated in patients with severe renal impairment or ESRD not yet on dialysis and matched healthy controls.
Conflicts of Interest
The financial arrangements of the authors with companies whose products may be related to the present report are listed below, as declared by the authors. R.B. and D.W. are employees of AbbVie Inc. and hold stock or stock options.
Funding
Allergan plc, Dublin, Ireland (prior to acquisition by AbbVie Inc.) funded the study. The wording “sponsored” was used in this section.
Supporting information
Supporting Information
Acknowledgments
Allergan plc, Dublin, Ireland (prior to acquisition by AbbVie Inc.) funded the study, contributed to the design, participated in the collection, analysis, and interpretation of data, and participated in writing and reviewing, and approved the final version. No honoraria or payments were made for authorship. All authors met International Committee of Medical Journal Editors authorship criteria. The authors wish to thank Edward Kaczynski, of AbbVie Inc., for his contributions to the manuscript. Writing and editorial assistance were provided to the authors by Elle Lindsay, PhD, and Jade Moores, MSc, of Complete HealthVizion, Inc., Chicago, IL, USA, and funded by AbbVie Inc.
Data Availability Statement
AbbVie is committed to responsible data sharing regarding the clinical studies we sponsor. This includes access to anonymized, individual and study‐level data (analysis data sets), as well as other information (eg, protocols and Clinical Study Reports), as long as the studies are not part of an ongoing or planned regulatory submission. This includes requests for clinical study data for unlicensed products and indications. This clinical study data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request visit the following link: https://www.abbvie.com/our‐science/clinical‐trials/clinical‐trials‐data‐and‐information‐sharing/data‐and‐information‐sharing‐with‐qualified‐researchers.html.
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