Randomized study of the effect of gadopiclenol, a new gadolinium-based contrast agent, on the QTc interval in healthy subjects

Abstract

Aims: 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.

Methods: 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^-1 , standard for current gadolinium-based contrast agents, the supraclinical dose of 0.3 mmol kg^-1 , placebo and a single oral dose of 400 mg moxifloxacin.

Results: The largest time-matched placebo-corrected, mean change from-baseline in QTcF (ΔΔQTcF) was observed 3 hours after administration of 0.1 mmol kg^-1 gadopiclenol (2.39 ms, 90% confidence interval [CI]: 0.35, 4.43 ms) and 5 minutes after administration of 0.3 mmol kg^-1 (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^-1 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.

Conclusion: 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.

Keywords: QTc interval; gadopiclenol; healthy subjects; osmolarity; thorough QT study.

FIGURE 1

Time‐matched, placebo‐corrected change from baseline in QTcF (ΔΔQTcF). Data are presented as time‐matched least square differences between study drugs and placebo and their corresponding 90% confidence interval. ▲‐▲, 0.1 mmol kg⁻¹ i.v. gadopiclenol, ■‐■, 0.3 mmol kg⁻¹ i.v. gadopiclenol, ●‐●, 400 mg oral moxifloxacin. The threshold of 10 ms is shown as a dotted horizontal line

FIGURE 2

Plasma concentration–time profiles of gadopiclenol. Data are presented as arithmetic mean ± standard deviation. ▲‐▲, 0.1 mmol kg⁻¹ i.v. gadopiclenol, ■‐■, 0.3 mmol kg⁻¹ i.v. gadopiclenol

FIGURE 3

Model‐predicted effect of gadopiclenol on baseline‐ and placebo‐corrected QTcF (ΔΔQTcF) over a concentration range of 0–4000 μg mL⁻¹. The ΔΔQTcF at the doses of 0.1 mmol kg⁻¹ (▲) and 0.3 mmol kg⁻¹ (■) are shown with their respective 90% confidence interval. The lines represent the model‐predicted linear relationship between concentration and effect on ΔΔQTcF and the lower and upper 90% confidence interval