Börje Darpö1, Mark Pirner2, James Longstreth3, Georg Ferber4. 1. Department of Clinical Sciences, Karolinska Institute, Danderyd's Hospital, 182 88 Stockholm, Sweden. Electronic address: borje.darpo@telia.com. 2. Department of Clinical Research and Medical Affairs, US WorldMeds, LLC, 4441 Springdale Rd, Louisville, KY 40241, USA. 3. Longstreth and Associates, Inc., 450 N Lakeshore Dr, Mundelein, IL 60060, USA. 4. Statistik Georg Ferber GmbH, Cagliostrostrasse 14, 4125 Riehen, Switzerland.
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.
RCT Entities:
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.
Authors: Charles W Gorodetzky; Sharon L Walsh; Peter R Martin; Andrew J Saxon; Kristen L Gullo; Kousick Biswas Journal: Drug Alcohol Depend Date: 2017-05-10 Impact factor: 4.492
Authors: Ivan Urits; Anjana Patel; Robbie Zusman; Celina Guadalupe Virgen; Mohammad Mousa; Amnon A Berger; Hisham Kassem; Jai Won Jung; Jamal Hasoon; Alan D Kaye; Omar Viswanath Journal: Psychopharmacol Bull Date: 2020-07-23