Funck-Brentano Christian, Felices Mathieu, Le Fur Nathalie, Dubourdieu Corinne, Desché Pierre, Vanhoutte Frédéric, Voiriot Pascal
INSERM, CIC-1901 and UMRS 1166, Paris, France; AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology and CIC-1901, Paris, France; Sorbonne Université Médecine, Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
Phinc, Massy, France.
Br J Clin Pharmacol. 2020 Nov;86(11):2174-2181. doi: 10.1111/bcp.14309. Epub 2020 Apr 27.
We investigated the effect of gadopiclenol, a new gadolinium-based contrast agent, on the QTc interval at clinical and supraclinical dose, considering the relative hyperosmolarity of this product.
This was a single centre, randomized, double-blind, placebo- and positive-controlled, 4-way crossover study. Forty-eight healthy male and female subjects were included to receive single intravenous (i.v.) administrations of gadopiclenol at the clinical dose of 0.1 mmol kg , standard for current gadolinium-based contrast agents, the supraclinical dose of 0.3 mmol kg , placebo and a single oral dose of 400 mg moxifloxacin.
The largest time-matched placebo-corrected, mean change from-baseline in QTcF (ΔΔQTcF) was observed 3 hours after administration of 0.1 mmol kg gadopiclenol (2.39 ms, 90% confidence interval [CI]: 0.35, 4.43 ms) and 5 minutes after administration of 0.3 mmol kg (4.81 ms, 90%CI: 2.84, 6.78 ms). The upper limit of the 90% CI was under the threshold of 10 ms, demonstrating no significant effect of gadopiclenol on QTc interval. From 1.5 to 4 hours postdose moxifloxacin, the lower limit of the 90% CI of ΔΔQTcF exceeded 5 ms demonstrating assay sensitivity. Although there was a positive slope, the concentration-response analysis estimated that the values of ΔΔQTcF at the maximal concentration of gadopiclenol at 0.1 and 0.3 mmol kg were 0.41 and 2.23 ms, respectively, with the upper limit of the 90% CI not exceeding 10 ms. No serious or severe adverse events or treatment discontinuations due to adverse events were reported.
This thorough QT/QTc study demonstrated that gadopiclenol did not prolong the QT interval at clinical and supraclinical doses and was well tolerated in healthy volunteers. The positive slope of the QTc prolongation vs concentration relationship suggests that hyperosmolarity could be associated with QTc prolongation. However, the amplitude of this effects is unlikely to be associated with proarrhythmia.
鉴于新型钆基造影剂加多普利醇的相对高渗性，我们研究了其在临床剂量和超临床剂量下对QTc间期的影响。
这是一项单中心、随机、双盲、安慰剂和阳性对照的四交叉研究。纳入48名健康男性和女性受试者，分别接受临床剂量0.1 mmol/kg（当前钆基造影剂的标准剂量）、超临床剂量0.3 mmol/kg的加多普利醇单次静脉注射，以及安慰剂和400 mg莫西沙星单次口服。
在给予0.1 mmol/kg加多普利醇后3小时（2.39 ms，90%置信区间[CI]：0.35，4.43 ms）和给予0.3 mmol/kg后5分钟（4.81 ms，90%CI：2.84，6.78 ms）观察到最大的与时间匹配的安慰剂校正后QTcF（ΔΔQTcF）自基线的平均变化。90%CI的上限低于10 ms的阈值，表明加多普利醇对QTc间期无显著影响。在莫西沙星给药后1.5至4小时，ΔΔQTcF的90%CI下限超过5 ms，表明检测具有敏感性。尽管存在正斜率，但浓度-反应分析估计，在0.1和0.3 mmol/kg加多普利醇最大浓度时，ΔΔQTcF值分别为0.41和2.23 ms，90%CI上限不超过10 ms。未报告严重或重度不良事件，也未因不良事件而停药。
这项全面的QT/QTc研究表明，加多普利醇在临床和超临床剂量下均未延长QT间期，且在健康志愿者中耐受性良好。QTc延长与浓度关系的正斜率表明，高渗性可能与QTc延长有关。然而，这种效应的幅度不太可能与心律失常相关。
