Effect of lofexidine on cardiac repolarization during treatment of opioid withdrawal

Abstract

Background: Lofexidine is a non-opioid treatment for opioid withdrawal syndrome. Its sympatholytic actions counteract the nor-adrenergic hyperactivity that occurs during abrupt opioid withdrawal.

Methods: The effect of lofexidine 2.16 and 2.88 mg/day on QTcF (QT interval, heart-rate corrected, Fridericia formula) was studied as part of a large, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT01863186). ECGs were time-matched to blood sampling for lofexidine concentration and were collected at prespecified timepoints over a 7-day inpatient period. Analyses included mean change-from-baseline QTcF and exposure-response modeling to predict QTcF at relevant lofexidine concentrations.

Results: A total of 681 adult men and women received at least 1 dose of study drug; 566 qualified for inclusion in the concentration-QTcF analysis. Most subjects were withdrawing from heroin. During the first 24 h (Days 1-2) post-baseline, small increases in QTcF were observed in all groups: 4.7 ms for lofexidine 2.16 mg, 7.4 ms for lofexidine 2.88 mg and 1.4 ms for placebo. These increases were transient; by Day 4, when lofexidine levels had reached steady-state, QTcF increases were not present. By Day 7, QTcF was decreased from baseline in all groups. Exposure-response modeling predicted <10 ms increases in QTcF at lofexidine concentrations 3 times those obtained at maximal recommended dose.

Conclusions: Lofexidine was associated with small, transient QTcF increases. Decreases in QTcF that occurred with higher lofexidine concentrations argue for an indirect QTcF effect, potentially from changes in autonomic tone. Both opioid withdrawal and lofexidine's sympatholytic actions would be expected to alter sympathetic outflow over the 7-day withdrawal.

Keywords: Exposure-Response modeling; Lofexidine; Opioid withdrawal; QTc; QTcF.

Conflict of interest statement

Conflicts of Interest

Börje Darpö is a consultant for iCardiac/ERT and owns stock in ERT. Mark Pirner is an employee of US WorldMeds. James Longstreth is a consultant to US WorldMeds, LLC. Georg Ferber is an independent consultant working for clinical research organizations.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1.

Study flow diagram. a The C-QTcF population included subjects with baseline and at least 1 on-treatment QTcF value with a plasma concentration value from the same time point (within 30 minutes) and with no measurable lofexidine plasma concentration at baseline.LFX, lofexidine.

Figure 2.

Change-from-baseline QTcF (ΔQTcF, ms) and mean lofexidine plasma concentration by timepoint. On Day 1 and in the morning of Day 2, a small prolongation of the QTcF interval is seen in both lofexidine groups; with continued dosing, ΔQTcF is reduced and prolongation is not observed on Day 7. LFX, lofexidine.

Figure 3.

Predicted QT effect (placebo-corrected ΔQTcF, ms) across lofexidine plasma concentrations based on the (A) linear model with baseline and (B) Emax model with baseline.Goodness-of-fit plot with predicted effect on ΔQTcF, with 90% confidence intervals (90% CI; black line with grey shaded area). The ΔQTcF values are adjusted for the placebo response and correspond to placebo-corrected ΔQTcF as used in other analyses. The horizontal bars near the lower edge of the figures show the lofexidine plasma concentration decile breakpoints (hatch marks). The vertical bars and whiskers show the interquartile ranges about the observed median placebo-corrected ΔQTcF (solid circles) within each concentration decile. The shaded areas between the two curvilinear lines in each graph show the 90% CI for the ΔQTcF as calculated from the two models. Both models predict a small QT effect with increasing lofexidine plasma concentrations. With the linear model, an effect on placebo-corrected ΔQTcF larger than 10 ms can be excluded up to lofexidine plasma concentrations of ~10 ng/mL.

Figure 4.

Change-from-baseline QTcF (ΔQTcF, ms) by completer status. The same pattern of mild QTc prolongation on Day 1 that disappears with continued dosing was seen in subjects with data from all days, i.e., up to and including Day 7, as compared to the full study population (Figure 2). In subjects with data on Days 1 and 2 only, the effect on ΔQTcF was somewhat more pronounced in the lofexidine 2.88 mg group. LFX, lofexidine.