Paul Covington

Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes.

BACKGROUND Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes (T2D). OBJECTIVES This study was conducted to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles and explore the efficacy of multiple oral doses of alogliptin in patients with T2D. METHODS In this randomized, double-blind, placebo-controlled, parallel-group study, patients with T2D between the ages of 18 and 75 years were assigned to receive a single oral dose of alogliptin 25, 100, or 400 mg or placebo (4:4:4:3 ratio) once daily for 14 days. PK profiles and plasma DPP-4 inhibition were assessed on days 1 and 14. Tolerability was monitored based on adverse events (AEs) and clinical assessments. Efficacy end points included 4-hour postprandial plasma glucose (PPG) and insulin concentrations, and fasting glycosylated hemoglobin (HbA(1c)), C-peptide, and fructosamine values. RESULTS Of 56 enrolled patients (57% women; 93% white; mean age, 55.6 years; mean weight, 89.8 kg; mean body mass index, 31.7 kg/m(2)), 54 completed the study. On day 14, the median T(max) was ~1 hour and the mean t(1/2) was 12.5 to 21.1 hours across all alogliptin doses. Alogliptin was primarily excreted renally (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60.8%-63.4%). On day 14, mean peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24 hours after dosing ranged from 82% to 97% across all alogliptin doses. Significant decreases from baseline to day 14 were observed in mean 4-hour PPG after breakfast with alogliptin 25 mg (-32.5 mg/dL; P=0.008), 100 mg (-37.2; P=0.002), and 400 mg (-65.6 mg/dL; P<0.001) compared with placebo (+8.2 mg/dL). Significant decreases in mean 4-hour PPG were also observed for alogliptin 25, 100, and 400 mg compared with placebo after lunch (-15.8 mg/dL [P=0.030]; -29.2 mg/dL [P=0.002]; -27.1 mg/dL [P=0.009]; and +14.3 mg/dL, respectively) and after dinner (-21.9 mg/dL [P=0.017]; -39.7 mg/dL [P<0.001]; -35.3 mg/dL [P=0.003]; and +12.8 mg/dL). Significant decreases in mean HbA(1c) from baseline to day 15 were observed for alogliptin 25 mg (-0.22%; P=0.044), 100 mg (-0.40%; P<0.001), and 400 mg (-0.28%; P=0.018) compared with placebo (+0.05%). Significant decreases in mean fructosamine concentrations from baseline to day 15 were observed for alogliptin 100 mg (-25.6 micromol/L; P=0.001) and 400 mg (-19.9 micromol/L; P=0.010) compared with placebo (+15.0 micromol/L). No statistically significant changes were noted in mean 4-hour postprandial insulin or mean fasting C-peptide. No serious AEs were reported, and no patients discontinued the study because of an AE. The most commonly reported AEs for alogliptin 400 mg were headache in 6 of 16 patients (compared with 0/15 for alogliptin 25 mg, 1/14 for alogliptin 100 mg, and 3/11 for placebo), dizziness in 4 of 16 patients (compared with 1/15, 2/14, and 1/11, respectively), and constipation in 3 of 16 patients (compared with no patients in any other group). No other individual AE was reported by >2 patients receiving the 400-mg dose. Apart from dizziness, no individual AE was reported by >1 patient receiving either the 25- or 100-mg dose. CONCLUSIONS In these adult patients with T2D, alogliptin inhibited plasma DPP-4 activity and significantly decreased PPG levels. The PK and PD profiles of multiple doses of alogliptin in this study supported use of a once-daily dosing regimen. Alogliptin was generally well tolerated, with no dose-limiting toxicity.

Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects.

BACKGROUND Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. OBJECTIVE This study was conducted to characterize the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of alogliptin in healthy male subjects. METHODS This was a randomized, double-blind, placebo-controlled study in which healthy, nonobese male subjects between the ages of 18 and 55 years were assigned to 1 of 6 cohorts: alogliptin 25, 50, 100, 200, 400, or 800 mg. One subject in each cohort received placebo. An ascending-dose strategy was used, in which each cohort received its assigned dose only after review of the safety data from the previous cohort. Blood and urine were collected over 72 hours after dosing for pharmacokinetic analysis and determination of plasma DPP-4 inhibition and active glucagon-like peptide -1(GLP-1) concentrations. RESULTS Thirty-six subjects (66 per cohort) were enrolled and completed the study (29/36 [81% ] white; mean age, 26.6 years; mean weight, 76.0 kg). Alogliptin was rapidly absorbed (median T(max), 1-2 hours) and eliminated slowly (mean t(1/2), 12.4-21.4 hours), primarily via urinary excretion (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60%-71%). C(max) and AUC(0-infinity) increased dose proportionally over the range from 25 to 100 mg. The metabolites M-I (N-demethylated) and M-II (N-acetylated) accounted for <2% and <6%, respectively, of alogliptin concentrations in plasma and urine. Across alogliptin doses, mean peak DPP-4 inhibition ranged from 93% to 99%, and mean inhibition at 24 hours after dosing ranged from 74% to 97%. Exposure to active GLP-1 was 2- to 4-fold greater for all alogliptin doses compared with placebo; no dose response was apparent. Hypoglycemia (asymptomatic) was reported in 5 subjects (11 receiving alogliptin 50 mg, 2 receiving alogliptin 200 mg, 1 receiving alogliptin 400 mg, 1 receiving placebo). Other adverse events were reported in 1 subject each: dizziness (alogliptin 100 mg), syncope (alogliptin 200 mg), constipation (alogliptin 200 mg), viral infection (alogliptin 400 mg), hot flush (placebo), and nausea (placebo). CONCLUSION In these healthy male subjects, alogliptin at single doses up to 800 mg inhibited plasma DPP-4 activity, increased active GLP-1, and was generally well tolerated, with no dose-limiting toxicity.

Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline

The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS‐d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased eluxadoline systemic exposure [AUC(0–inf)] by 4.4‐ and 1.4‐fold, respectively, whereas peak exposure (Cmax) increased 6.2‐fold and 1.3‐fold, respectively. Cyclosporine had little effect on renal clearance (CLren) of eluxadoline whereas probenecid reduced CLren by nearly 50%. These study results suggested that sinusoidal OATP1B1‐mediated hepatic uptake of eluxadoline (during first‐pass and systemic extraction) plays a major role in its absorption and disposition, whereas OAT3‐mediated basolateral uptake in the proximal renal tubules and MRP2‐mediated canalicular and renal tubular apical efflux play only minor roles in its overall disposition. All treatments were safe and well tolerated.

Item-Level Assessment of the Irritable Bowel Syndrome Quality of Life Questionnaire in Patients With Diarrheal Irritable Bowel Syndrome

BACKGROUND In previous studies, the Irritable Bowel Syndrome Quality of Life (IBS-QOL) instrument has been determined to have good measurement properties for general irritable bowel syndrome (IBS) and the diarrheal IBS (IBS-d) subtype in clinical trials. OBJECTIVE This article aims to extend the true-score analyses that have been previously conducted to evaluate the IBS-QOL in IBS-d patients. METHODS Item response theory analysis was conducted by fitting models to responses from 753 patients with severe IBS-d from a recent clinical trial. Three item response theory models, the constrained graded response model (CGRM), the unconstrained GRM (UGRM), and the testlet response model (TRM), were fit to the 34 items of the IBS-QOL questionnaire. Subsequently, differential item functioning (DIF) for patient sex was assessed by fitting nested models by applying likelihood ratio tests. Model latent trait estimates were then compared with the IBS-QOL score and the IBS Symptom Severity Score. RESULTS Model fits improved with complexity, with the TRM model fitting best compared with the CGRM and UGRM. The DIF evaluation for patient sex flagged 17 items for the CGRM and 9 items for the UGRM; however, these items were not found to have much effect on the overall estimation of the latent trait. Differential testlet functioning was not indicated, and no items exhibited potential DIF under the TRM because likelihood ratio tests were not statistically significant. Comparison of latent trait estimates to the IBS Symptom Severity Score and IBS-QOL questionnaire revealed high Spearman correlations (0.47 and ≥0.99, respectively). CONCLUSION Previous true-score approach results were supported by the IBS-QOL item-level analysis. Further, the IBS-QOL total score was found to be a valid measure of perceived quality of life for IBS-d patients when compared with more sophisticated model-based estimates of perceived quality of life. ClinicalTrials.gov identifier: NCT01130272.

Sphincter of Oddi Function and Risk Factors for Dysfunction

The sphincter of Oddi (SO) is a smooth muscle valve regulating the flow of biliary and pancreatic secretions into the duodenum, initially described in 1887 by the Italian anatomist, Ruggero Oddi. SO dysfunction (SOD) is a broad term referring to numerous biliary, pancreatic, and hepatic disorders resulting from spasms, strictures, and relaxation of this valve at inappropriate times. This review brings attention to various factors that may increase the risk of SOD, including but not limited to: cholecystectomy, opiates, and alcohol. Lack of proper recognition and treatment of SOD may be associated with clinical events, including pancreatitis and biliary symptoms with hepatic enzyme elevation. Pharmacologic and non-pharmacologic approaches are discussed to help recognize, prevent, and treat SOD. Future studies are needed to assess the treatment benefit of agents such as calcium-channel blockers, glyceryl trinitrate, or tricyclic antidepressants in patients with SOD.

Eluxadoline Demonstrates a Lack of Abuse Potential in Phase 2 and 3 Studies of Patients With Irritable Bowel Syndrome With Diarrhea

BACKGROUND & AIMS Eluxadoline is approved by the Food and Drug Administration for the treatment of adults with irritable bowel syndrome with diarrhea (IBS‐D). Eluxadoline is a locally acting mixed &mgr;‐opiod and &kgr;‐opioid receptor agonist and &dgr;‐opioid receptor antagonist. The abuse potential of eluxadoline was evaluated as part of the Phase 2 and 3 clinical trials assessing the efficacy, safety, and tolerability of the drug. METHODS One Phase 2 (IBS‐2001) and two Phase 3 (IBS‐3001 and IBS‐3002) randomized controlled trials enrolled patients meeting Rome III criteria for IBS‐D. Patients received oral twice‐daily double‐blind treatment with eluxadoline or placebo for 12, 26, or 52 weeks. The primary end point of these studies was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of days. Safety data were pooled, and specific adverse event terms potentially related to abuse were assessed descriptively. Adverse events reported during a 2‐week post‐treatment period (IBS‐3001) and a 4‐week single‐blind washout period (IBS‐3002) were assessed for signs of opioid withdrawal. Potential withdrawal effects were assessed by using the Subjective Opiate Withdrawal Scale. RESULTS Overall, 807 and 1032 patients received 1 or more doses of eluxadoline (75 or 100 mg, respectively), and 975 patients received placebo. The overall incidence of adverse events potentially related to abuse did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (2.8%, 2.7%, and 4.3%, respectively). The most common adverse events potentially related to abuse were anxiety and somnolence, which occurred in less than 2% of patients in each group. Median overall Subjective Opiate Withdrawal Scale scores did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (3.0, 2.0, and 3.0, respectively). CONCLUSIONS In an analysis of data from Phase 2 and Phase 3 trials of eluxadoline (75 or 100 mg) for patients with IBS‐D, data revealed no signs of abuse potential for eluxadoline. ClinicalTrials.gov numbers: NCT01130272, NCT01553591, NCT01553747.

Effect of Hepatic Impairment on Eluxadoline Pharmacokinetics

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by recurrent abdominal pain and altered bowel movements that is subtyped as predominantly diarrheal (IBS-D), constipating, or mixed/alternating between diarrhea and constipation.1 The global presence of IBS is approximately 11%, with one-third of all IBS cases being IBS-D.2,3 Patients with IBS-D commonly experience multiple symptoms, including bloating, abdominal pain, urgency, and diarrhea, ranging in levels of severity from mild and intermittent to severe and continuous.4 The burden of symptoms experienced by patients with IBS-D is associated with significant reductions in quality of life and increased use of healthcare resources.5,6 These burdens emphasize the need for pharmacological treatments to more effectively manage IBS-D symptoms. FDA-approved therapies for adults with IBS-D include eluxadoline, rifaximin, and alosetron (specifically for women with severe IBS-D).7 Eluxadoline (Viberzi; Furiex Pharmaceuticals, Inc, a subsidiary of Allergan plc, Parsippany, New Jersey) is a mixed μ-opioid receptor and κ-opioid receptor agonist and δ-opioid receptor antagonist that is locally active in the gastrointestinal tract.8 In 2 phase 3 clinical trials, eluxadoline 75mg and 100mg twice daily demonstrated efficacy in improving the abdominal pain and stool consistency associated with IBS-D, measured by a composite efficacy end point combining stool consistency and abdominal pain responses.9 Eluxadoline was well tolerated; clinical trials have shown that incidence rates of adverse events (AEs) and serious AEs were similar between eluxadoline-treated groups (at 75-mg and 100-mg doses) compared with those receiving placebo.10 The most common yet infrequent AE was constipation; discontinuation due to constipation was low. Treatment-emergent AEs tended to occur within the first few weeks after initiation of treatment. In nonclinical studies of cannulated rats low levels of eluxadoline were detectable in the hepatic portal vein after oral administration, although concentrations in the jugular vein were mostly below detectable levels.11 Additional evidence demonstrated that eluxadoline has poor oral bioavailability in humans (1.02%), primarily due to low gastrointestinal permeability (2.3%) but also resulting from hepatic first-pass extraction (55.8%).12 These results suggest that the liver plays an important role in the clearance of eluxadoline. The aim of this study, which was completed prior to the approval of eluxadoline, was therefore to determinewhether hepatic impairment has any clinically relevant effect on exposure to eluxadoline by assessment of the pharmacokinetic (PK), safety, and tolerability profile of a single oral dose of eluxadoline.

Safety of Eluxadoline in Patients with IBS-D Without a Gallbladder

higher dose of 100 mg BID, and the lower approved dose of 75 mg BID was recommended for patients without a gallbladder. Since the approval of eluxadoline in May 2015 through February 2017, 120 serious cases of pancreatitis or death were reported via the FDA Adverse Event Reporting System ( 2 ). During this period, ~79,600 patients were treated with eluxadoline. Among the 68 patients with reported gallbladder status, 56 did not have a gallbladder. Two deaths occurred in patients with pancreatitis, and a third death occurred in a patient with elevated liver and pancreatic enzymes; all three patients were cholecystectomized. Both patients with pancreatitis had additional risk factors for pancreatitis; one had a history of hereditary pancreatitis and was taking fentanyl and pancreatic enzymes, and the other had a body mass index of 38.5 kg/m 2 . Th e third patient suffered a cardiac arrest and had a history of hypertension. Th is label change emphasizes the importance of post-marketing surveillance. In fact, 32% of therapeutics approved by the FDA from 2001 through 2010 had a post-market safety event ( 3 ). However, incomplete case details may preclude full evaluation of reported events. For eluxadoline, full case details, particularly alcohol use, which is a risk factor for pancreatitis, were oft en unavailable. Indeed, eluxadoline is contraindicated in patients with alcohol abuse, addiction, or excessive consumption. It was also reported that 21% of patients without a gallbladder received a dose of eluxadoline other than the then recommended dose of 75 mg BID. Th e underlying cause of SO dysfunction and pancreatitis in patients without a gallbladder remains unclear, although cholecystectomy is associated with suppression of cholecystokinin-mediated inhibition of SO phasic activity ( 4 ). SO spasm is a known eff ect of μ -opioid receptor agonists ( 5 ), and the μ -opioid receptor agonist activity of eluxadoline may therefore further increase SO tone in cholecystectomized patients, increasing the risk of adverse events. In summary, eluxadoline is now contraindicated in patients without a gallbladder, but remains an eff ective and well-tolerated therapy for appropriately selected patients with IBS-D. 6. Wu BU , Batech M , Quezada M et al. Dynamic measurement of disease activity in acute pancreatitis: the pancreatitis activity scoring system . Am J Gastroenterol 2017 ; 112 : 1144 – 52 .

Su1384 A Retrospective Assessment of Area Under the Pain Curve in Quantifying Daily Pain Assessments in Irritable Bowel Syndrome With Diarrhea

Background & Aims: Eluxadoline (ELX) is a locally active, mixed mu opioid receptor agonist and delta opioid receptor antagonist which was shown to improve the symptoms of irritable bowel syndrome with diarrhea (IBS-D) in 2 Phase 3 trials. With respect to abdominal pain, we performed additional prospective analyses to further examine efficacy on pain in IBS-D. Methods: Two double-blind, placebo-controlled, Phase 3 clinical trials (3001 and 3002) enrolled patients meeting Rome III criteria for IBS-D to twice-daily treatment with ELX (75 or 100 mg) or placebo (PBO). Both clinical trials had identical designs through 26 weeks of treatment. The primary endpoint was a composite response based on simultaneous daily improvement in worst abdominal pain (WAP) and stool consistency over Weeks 1-12 (Food and Drug Administration [FDA] endpoint) and Weeks 1-26 (European Medicines Agency [EMA] endpoint). Additional prospective analyses of WAP (scale of 010) included: Cochran-Mantel-Haenszel (CMH) assessments of WAP responders, defined as patients with ≥50% of days with ≥30% improvement (at the study level and pooled); longitudinal analyses (LA) of WAP response rates and of WAP daily scores, both at specific time points and at the study level; assessment of pooled data using CMH analyses of WAP responders over the 2 intervals based on 40% and 50% improvements in pain; and analysis of covariance (ANCOVA) assessment of change from baseline (CFB) in WAP daily scores of the pooled data at specific time points. Results: 2428 patients with IBS-D were enrolled across the 2 trials. Significantly more patients receiving ELX (75 mg and 100 mg) were FDA and EMA responders compared with patients receiving PBO (p 30% pain improvement for >50% of days), significant differences between ELXand PBO-treated patients were present for LA of WAP responders at Week 26 for ELX 75 mg in both studies and for ELX 100 mg in Study 3002 (Table 1). Likewise, LA of WAP scores at Week 26 achieved significance for ELX 100 mg in both studies at both time points. CMH analyses from the pooled data showed significant differences for ELX 100 mg over PBO for WAP responders at both the >40% and >50% pain improvement levels (Table 2). Findings were similar for the ANCOVA CFB WAP score analysis of the pooled data. Conclusions: Results from 2 Phase 3 clinical trials demonstrated that ELX showed statistically significant improvement in treating the abdominal pain component of IBS-D. This was particularly evident for ELX 100 mg, with ≥40% pain improvement definition for responders. This was further supported by results of the LA of pain response rates and LA of pain scores at the study level and ANCOVACFB analyses from the pooled data. Table 1. Study-specific pain analyses

Evaluation of Eluxadoline Effect on Cardiac Repolarization

This study evaluated the effects of eluxadoline, a mixed μ‐opioid receptor (OR) and κ‐OR agonist and δ‐OR antagonist, on cardiac repolarization. This evaluator‐blinded, placebo‐ and positive‐controlled, 4‐period crossover study randomized healthy men and women to single oral doses of eluxadoline (therapeutic dose 100 mg or supratherapeutic dose 1000 mg), moxifloxacin 400 mg, or placebo. QT data were corrected using individual custom correction (QTcI). The primary endpoint was the change from baseline in QTcI intervals (ΔQTcI) between eluxadoline and placebo (ΔΔQTcI). An upper bound of the 95% confidence interval around ΔΔQTcI of 10 milliseconds was considered clinically significant. Concentration–QTc data were analyzed using a repeated‐measures, mixed‐effects linear model. Sixty‐four volunteers were treated, and 58 completed the study. Assay sensitivity was demonstrated with moxifloxacin (noted by ΔΔQTcI of 11.94 milliseconds). The maximum ΔΔQTcI for eluxadoline 1000 mg was 4.10 milliseconds 1 hour postdose (1‐sided 95% upper confidence bound, 5.81 milliseconds), and for eluxadoline 100 mg was 1.20 milliseconds at 0.5 hours postdose (1‐sided 95% upper confidence bound, 2.91 milliseconds). Primary ΔΔQTcI results were confirmed using Fridericias formula for QTc. Categorical, morphological, and concentration–QTc analyses were consistent with the primary and secondary findings. There were no significant gender effects on ΔΔQTcI values. The most common adverse events were contact dermatitis and nausea (12.5% each) and dizziness (10.9%); adverse events were more frequent in the eluxadoline 1000 mg group. In conclusion, eluxadoline, at therapeutic or supratherapeutic doses, did not significantly prolong QT intervals, and was safe and generally well tolerated in this study population.