Division of Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana.
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università "Federico II" di Napoli, Naples, Italy.
Endocr Pract. 2024 Jan;30(1):11-18. doi: 10.1016/j.eprac.2023.09.011. Epub 2023 Oct 5.
To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc).
Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling.
Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc.
At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.
评估一种正在研究用于治疗内源性皮质醇过多症（库欣综合征[CS]）患者的选择性糖皮质激素受体调节剂 relacorilant 对心率校正 QT 间期（QTc）的影响。
纳入了 relacorilant 的三项临床研究：（1）一项在健康志愿者中进行的首次人体、随机、安慰剂对照、递增剂量（最高达 500 mg relacorilant）研究；（2）一项在健康志愿者中进行的 400 和 800 mg relacorilant 的安慰剂和阳性对照全面 QTc（TQT）研究；以及（3）一项在 CS 患者中进行的为期 16 周、每日最高达 400 mg relacorilant 的开放标签 2 期研究。进行了心电图记录，并计算了从基线（ΔQTc）的 QTc 变化。使用线性混合效应模型评估健康志愿者中血浆 relacorilant 浓度与 QTc 影响的相关性。
在所有研究中，未观察到心电图参数的明显变化。在所有时间点和所有 relacorilant 剂量下，包括治疗剂量，ΔQTc 较小，通常为负值，并且在安慰剂对照研究中与安慰剂相似。在 TQT 研究中，relacorilant 的安慰剂校正 ΔQTc 较小且为负值，而莫西沙星阳性对照的安慰剂校正 ΔQTc 显示出快速的 QTc 延长。这些结果构成了一项阴性 TQT 研究。浓度-QTc 关系模型估计的斜率略为负值，排除了 relacorilant 与 QTc 延长相关的可能性。
在所有研究剂量下，relacorilant 始终在健康志愿者和 CS 患者中显示出缺乏 QTc 延长，包括在 TQT 研究中。正在进行的 3 期研究将有助于进一步确定 relacorilant 的总体获益-风险特征。
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