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

Abstract

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 positivecontrolled, 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.

Pharmacokinetics, Safety, and Efficacy of Gadopiclenol in Pediatric Patients Aged 2 to 17 Years

“…In accordance with previous results from 4 published clinical trials including adult healthy volunteers, patients with brain lesions, and patients with renal impairment, 7–10 this study showed a good safety profile of gadopiclenol when used in pediatric patients aged 2 to 17 years, with only 2 nonserious AEs related to gadopiclenol (a mild QT interval prolongation and a moderate maculopapular rash). In a thorough QT/QTc phase I, randomized, double-blind study performed on 48 adult healthy volunteers, it has been shown that gadopiclenol did not prolong QT interval at clinical (0.1 mmol/kg) and supraclinical (0.3 mmol/kg) doses 10 …”

“…[17][18][19][20] In a previous phase IIb, double-blind, randomized study performed on adults, it has been shown that lesion border delineation, internal morphology, and contrast enhancement of CNS lesions were not significantly different with gadopiclenol used at 0.05 mmol/kg and gadobenate dimeglumine (the approved GBCA at the time of the study with the highest relaxivity) used at 0.1 mmol/kg. 9 In accordance with previous results from 4 published clinical trials including adult healthy volunteers, patients with brain lesions, and patients with renal impairment, [7][8][9][10] this study showed a good safety profile of gadopiclenol when used in pediatric patients aged 2 to 17 years, with only 2 nonserious AEs related to gadopiclenol (a mild QT interval prolongation and a moderate maculopapular rash). In a thorough QT/ QTc phase I, randomized, double-blind study performed on 48 adult healthy volunteers, it has been shown that gadopiclenol did not prolong QT interval at clinical (0.1 mmol/kg) and supraclinical (0.3 mmol/kg) doses.…”

“…8 Results from 4 published clinical trials, including a total of 392 adult subjects (healthy volunteers, patients with brain lesions, and patients with renal impairment), showed that gadopiclenol presents a good biological and clinical safety profile. [7][8][9][10] The aim of this trial was to investigate the pharmacokinetic (PK) profile of gadopiclenol at 0.05 mmol/kg after a single intravenous injection and to evaluate its safety and efficacy in pediatric patients aged 2 to 17 years.…”

“…Results from 4 published clinical trials, including a total of 392 adult subjects (healthy volunteers, patients with brain lesions, and patients with renal impairment), showed that gadopiclenol presents a good biological and clinical safety profile 7–10 …”

How the Chemical Properties of GBCAs Influence Their Safety Profiles In Vivo

“… a Based on the EMA recommendation [ 123 , 124 ]. b Low risk by design [ 57 , 58 , 125 , 126 , 127 , 128 ], no T 1 hyperintensity in animal models [ 56 , 126 , 129 ]. …”