Department of Clinical Sciences, Karolinska Institute, Danderyd's Hospital, 182 88 Stockholm, Sweden.
Department of Clinical Research and Medical Affairs, US WorldMeds, LLC, 4441 Springdale Rd, Louisville, KY 40241, USA.
Drug Alcohol Depend. 2019 Dec 1;205:107596. doi: 10.1016/j.drugalcdep.2019.107596. Epub 2019 Sep 27.
Lofexidine is a non-opioid treatment for opioid withdrawal syndrome. Its sympatholytic actions counteract the nor-adrenergic hyperactivity that occurs during abrupt opioid withdrawal.
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.
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.
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.
可乐定是一种非阿片类药物治疗阿片类戒断综合征。它的交感神经阻滞作用对抗了阿片类药物戒断时发生的去甲肾上腺素过度活跃。
作为一项大型、双盲、安慰剂对照试验（ClinicalTrials.gov 标识符：NCT01863186）的一部分，研究了可乐定 2.16 和 2.88mg/天对 QTcF（QT 间期，心率校正，Fridericia 公式）的影响。ECG 与可乐定浓度的血样时间匹配，并在 7 天住院期间的预定时间点采集。分析包括从基线 QTcF 的平均变化和暴露-反应建模，以预测相关可乐定浓度下的 QTcF。
共有 681 名成年男女接受了至少 1 次研究药物治疗；566 名符合纳入浓度-QTcF 分析的条件。大多数受试者正在从海洛因中戒断。在基线后的前 24 小时（第 1-2 天），所有组的 QTcF 都观察到了小的增加：可乐定 2.16mg 组为 4.7ms，可乐定 2.88mg 组为 7.4ms，安慰剂组为 1.4ms。这些增加是短暂的；到第 4 天，当可乐定水平达到稳态时，不再存在 QTcF 增加。到第 7 天，所有组的 QTcF 均从基线下降。暴露-反应模型预测，在可乐定浓度增加 3 倍达到最大推荐剂量时，QTcF 增加<10ms。
可乐定与 QTcF 短暂、轻微的增加有关。随着可乐定浓度的升高，QTcF 降低，这表明 QTcF 存在间接作用，可能来自自主神经张力的变化。在 7 天的戒断过程中，阿片类药物戒断和可乐定的交感神经阻滞作用都会改变交感神经输出。
