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Evaluation of Eluxadoline Effect on Cardiac Repolarization.

ABSTRACT: This study evaluated the effects of eluxadoline, a mixed ?-opioid receptor (OR) and ?-OR agonist and ?-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 (?QTcI) between eluxadoline and placebo (??QTcI). An upper bound of the 95% confidence interval around ??QTcI 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 ??QTcI of 11.94 milliseconds). The maximum ??QTcI 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 ??QTcI 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 ??QTcI 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.

SUBMITTER: Bonifacio L

PROVIDER: S-EPMC6175186 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Evaluation of Eluxadoline Effect on Cardiac Repolarization.

Bonifacio Laura L Hunt Thomas L TL McIntyre Gail G Dove Leonard S LS Covington Paul S PS

Clinical pharmacology in drug development 20180416 7

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 bas ...[more]

PMID: 29659201

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Project description:Deutetrabenazine (Austedo) is indicated in adults for chorea associated with Huntington disease and tardive dyskinesia. Escalating deutetrabenazine doses were administered to healthy volunteers who were cytochrome P450 2D6 extensive/intermediate metabolizers (EMs) or poor metabolizers (PMs) to determine pharmacokinetic exposure of parent drug and active metabolites (α-dihydrotetrabenazine [α-HTBZ] and β-dihydrotetrabenazine [β-HTBZ]), and collect corresponding electrocardiograms (ECGs) for evaluation of the cardiodynamic effect using concentration-QTc (C-QTc) modeling. Participants (12 EMs, 24 PMs) received placebo or single doses of deutetrabenazine (24, 48, and 72 mg) to achieve plasma concentrations exceeding therapeutic range in both cohorts. Pharmacokinetic samples were obtained over 72 hours after dosing and were time matched with 12-lead ECGs extracted from continuous ECG recordings. C-QTc analysis, using linear mixed-effects modeling and model selection procedure, characterized the relationship between plasma concentrations of deutetrabenazine, deuterated α-HTBZ and β-HTBZ, and the change from baseline in QT interval corrected using Fridericia's formula. Deutetrabenazine exhibited linear kinetics, and a C-QTc model with deuterated α-HTBZ and β-HTBZ was selected to best describe the C-QTc relationship in pooled EM and PM data. This model predicted a placebo-corrected Fridericia corrected QT interval prolongation higher than 10 milliseconds can be excluded at concentrations associated with the maximum recommended doses in both populations. Adverse events increased with higher exposure as reflected by the higher event number in the PM cohort receiving 48 and 72 mg doses. No subject discontinued due to cardiac-related adverse events and no clinically relevant ECG findings were reported. Thus, this study found that deutetrabenazine does not have a clinically relevant effect on QT prolongation at maximum recommended doses in either cytochrome P450 2D6 EMs or PMs.

Dataset Information

Evaluation of Eluxadoline Effect on Cardiac Repolarization.

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Evaluation of Eluxadoline Effect on Cardiac Repolarization.

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