卡贝缩宫素对心脏复极的影响：一项在健康成人中进行的随机、安慰剂和阳性对照的QT/QTc研究。
完整摘要 · 中文译文
卡贝缩宫素是一种缩宫素受体激动剂，用于预防产后出血。虽然已知缩宫素会短暂延长QT/QTc间期，但卡贝缩宫素可靠的QTc数据有限。已知卡贝缩宫素会升高心率（HR），这可能影响QTc分析；因此，选择一种不会过度升高心率的剂量很重要。这项随机、安慰剂对照和阳性对照试验评估了在45分钟内单次静脉输注超治疗剂量（650 μg）卡贝缩宫素对健康成人（N = 42）心脏复极的影响。从给药前45分钟至给药后24小时连续记录心动态心电图（ECG）。主要终点是采用最合适的心率（HR）校正方法得出的安慰剂校正的QT间期较基线的变化（ΔΔQTc）。主要分析基于卡贝缩宫素血浆浓度与ΔΔQTc之间关系的暴露-反应建模，以识别在高临床暴露下≥10毫秒的效应。在卡贝缩宫素静脉输注期间，心率较基线的平均变化达到最大值16.7次/分。评估了多种心率校正方法，发现安慰剂校正的、优化的、个体化心率校正QT间期（oQTcI）是合适的。在单次静脉输注867 μg/h卡贝缩宫素后达到12.4 ng/mL的高临床暴露水平时，估计的安慰剂校正的oQTcI较基线的平均变化为4.5毫秒（90% CI: 3.4, 5.6）。卡贝缩宫素的暴露-反应模型未预测到具有临床或监管关注意义的QTc延长（≥ 10 msec）在临床高暴露水平下。试验注册：ClinicalTrials.gov 注册号：NCT05924321。
完整摘要 · 英文原文
Carbetocin is an oxytocin receptor agonist used for postpartum hemorrhage prevention. While oxytocin is known to transiently prolong the QT/QTc interval, robust QTc data for carbetocin are limited. Carbetocin is known to elevate HR, which can impact QTc analyses; thus, a dose that did not overly elevate HR was important to select. This randomized, placebo- and positive-controlled trial evaluated the effect of a single intravenous infusion of a supratherapeutic dose (650 μg) of carbetocin over 45 min on cardiac repolarization in healthy adults (N = 42). Continuous cardiodynamic ECGs were recorded from 45 min before through 24 h after dosing. The primary endpoint was placebo-corrected change from baseline in QT interval (ΔΔQTc) using the most appropriate heart rate (HR) correction method. The primary analysis was based on exposure-response modeling of the relationship between carbetocin plasma concentrations and ΔΔQTc, to identify an effect ≥ 10 msec at the high clinical exposure. During intravenous infusion of carbetocin, the mean HR change from baseline reached a maximum of 16.7 bpm. Multiple correction methods for HR were assessed, and the placebo-corrected, optimized, individualized heart rate-corrected QT interval (oQTcI) was found to be adequate. The estimated mean placebo-corrected oQTcI change from baseline was 4.5 msec (90% CI: 3.4, 5.6) at the high clinical exposure level of 12.4 ng/mL following a single intravenous infusion of 867 μg/h carbetocin. Exposure-response models for carbetocin established no predicted QTc prolongations of clinical or regulatory concern (≥ 10 msec) at the high clinical exposure level. Trial Registration: ClinicalTrials.gov Registration: NCT05924321.