Effect of Hepatic Impairment on Eluxadoline Pharmacokinetics

Marbury, Thomas; Berg, Jolene Kay; Dove, Leonard S.; Covington, Paul S.

doi:10.1002/jcph.964

Cited by 8 publications

(11 citation statements)

References 13 publications

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“…In human abuse liability studies, eluxadoline has been demonstrated to have lower oral or intranasal abuse potential in humans than does the centrally acting μ-OR agonist oxycodone. 15 Eluxadoline has demonstrated reduced clearance and increased exposure in patients with hepatic impairment 16 and is contraindicated in this patient group. 13,14 The low systemic absorption of eluxadoline is due to both poor absorption and moderate hepatic first-pass extraction, and results in a high degree of variability in PK parameters.…”

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confidence: 99%

“…OATP1B1‐mediated hepatic uptake has been suggested as the primary mode of clearance of eluxadoline, and although the metabolic pathways of eluxadoline remain unclear, caution is recommended with coadministration of strong cytochrome P450 (CYP) inhibitors (ie, ciprofloxacin, fluconazole, gemfibrozil) . Eluxadoline has demonstrated reduced clearance and increased exposure in patients with hepatic impairment and is contraindicated in this patient group.…”

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confidence: 99%

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Evaluation of Eluxadoline Effect on Cardiac Repolarization

Bonifacio

Hunt

McIntyre³

et al. 2018

Clinical Pharm in Drug Dev

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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 Fridericia's 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.

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confidence: 99%

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confidence: 99%

Evaluation of Eluxadoline Effect on Cardiac Repolarization

Bonifacio

Hunt

McIntyre³

et al. 2018

Clinical Pharm in Drug Dev

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“…Pharmacokinetic data indicate that for patients with mild to moderate hepatic impairment, the lower eluxadoline dose of 75 mg should be administered, given the sixfold and fourfold increases in systemic exposure (ie, mean area under the plasma concentration vs time curve to last measurable concentration) of single‐dose eluxadoline in adults with mild and moderate hepatic impairment (ie, Child‐Pugh class A and B, respectively) . A 16‐fold increase in systemic exposure was observed in adults with severe hepatic impairment (Child‐Pugh class C); eluxadoline is therefore contraindicated in these patients …”

Section: Resultsmentioning

confidence: 99%

Review article: an analysis of safety profiles of treatments for diarrhoea‐predominant irritable bowel syndrome

Lacy

2018

Aliment Pharmacol Ther

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“…For example, eluxadoline, a substrate of UDP-glucuronosyltransferase (UGT), organic anion-transporting polypeptide 1B1 (OATP1B1), organic anion transporter 3 (OAT3), and multidrug resistance-associated protein 2 (MRP2) showed a 13.7-fold increase in the AUC in severe hepatic impairment relative to a healthy state. 24 Paritaprevir, a CYP3A4 substrate, is affected greatly (>10fold increase in the AUC) in patients with hepatic impairment compared with healthy controls. 25 Other drugs that show >2-fold increase in the AUC in hepatic disease conditions are repaglinide, zidovudine, lamotrigine, ritonavir, dasabuvir, everolimus, and flibanserin.…”

Section: Impact Of Disease Conditions On Drug Disposition and The Potmentioning

confidence: 99%

Utility of Quantitative Proteomics for Enhancing the Predictive Ability of Physiologically Based Pharmacokinetic Models Across Disease States

Sharma

Ahire

2020

The Journal of Clinical Pharma

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Disease states such as liver cirrhosis and chronic kidney disease can lead to altered pharmacokinetics (PK) of drugs by influencing drug absorption, blood flow to organs, plasma protein binding, apparent volume of distribution, and drug-metabolizing enzyme and transporter (DMET) abundance. Narrow therapeutic index drugs are particularly vulnerable to undesired pharmacodynamics (PD) because of the changes in drug PK in disease states. However, systematic clinical evaluation of disease effect on drug PK and PD is not always possible because of the complexity or the cost of clinical studies. Physiologically based PK (PBPK) modeling is emerging as an alternate method to extrapolate drug PK from the healthy population to disease states. These models require information on the effect of disease condition on the activity or tissue abundance of DMET proteins. Although immunoquantification-based abundance data were available in the literature for a limited number of DMET proteins, the emergence of mass spectrometry-based quantitative proteomics as a sensitive, robust, and high-throughput tool has allowed a rapid increase in data availability on tissue DMET abundance in healthy versus disease states, especially in liver tissue. Here, we summarize these data including the available immunoquantification or mRNA levels of DMET proteins (healthy vs disease states) in extrahepatic tissue and discuss the potential applications of DMET abundance data in enhancing the capability of PBPK modeling in predicting drug disposition across disease states. Successful examples of PBPK modeling that integrate differences in DMET proteins between healthy and disease states are discussed.

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Effect of Hepatic Impairment on Eluxadoline Pharmacokinetics

Cited by 8 publications

References 13 publications

Evaluation of Eluxadoline Effect on Cardiac Repolarization

Evaluation of Eluxadoline Effect on Cardiac Repolarization

Review article: an analysis of safety profiles of treatments for diarrhoea‐predominant irritable bowel syndrome

Utility of Quantitative Proteomics for Enhancing the Predictive Ability of Physiologically Based Pharmacokinetic Models Across Disease States

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