Pharmacokinetics, Dialysability, and Safety of Gadopiclenol, a New Gadolinium-Based Contrast Agent, in Patients With Impaired Renal Function

Abstract

Objectives: The aims of this study were to evaluate the pharmacokinetics (PK) of gadopiclenol, a new macrocyclic gadolinium based-contrast agent, in subjects with impaired renal function, and to assess its dialysability in subjects with end-stage renal disease (ESRD). Methods and Materials: This 2-center, open-label, phase 1 study included 5 successive cohorts of 8 adult subjects: healthy subjects (cohort 1), subjects with mild (cohort 2), moderate (cohort 3), severe (cohort 4) renal impairment, or ESRD (cohort 5), who received a single intravenous injection of gadopiclenol (0.1 mmol/kg). Blood and urine samples were collected at different time points in cohorts 1 to 4, and blood and dialysate samples were collected at each hemodialysis session (4-hour session on day 1, day 3, and day 5) in cohort 5. Gadopiclenol elimination and safety were assessed for up to 6 months. Pharmacokinetics parameters were calculated using noncompartmental analysis. Results: A total of 40 subjects were included, with a mean age of 51.5 years (range, 18-71 years). No significant difference in the mean maximum concentration values and the distribution volume was observed among cohorts 1 to 4. Urinary excretion of unchanged gadopiclenol was delayed with the degree of renal impairment and ranged between 96% and 84% in subjects with mild to severe renal impairment. Compared with that of healthy subjects, the mean area under the plasma concentration curve was 54%, 148%, and 769% higher in subjects with mild, moderate, or severe renal impairment, respectively. The mean terminal half-life was prolonged with the degree of renal impairment (1.9, 3.3, 3.8, and 11.7 hours for cohorts 1-4). In ESRD subjects, gadopiclenol was effectively removed from the plasma (95% to 98%) after the first hemodialysis session. Gadopiclenol concentration in plasma was below the limit of quantification for all subjects after the second hemodialysis session. Gadopiclenol concentration was below limit of quantification in all plasma and urine samples collected at 1, 3, and 6 months. Five subjects (12.5%) experienced adverse events related to gadopiclenol, none serious and all resolved. Laboratory measurements, vital signs, and electrocardiography did not raise any safety concern. Conclusions: Gadopiclenol elimination half-life was prolonged in subjects with mild to severe renal impairment, yet its renal clearance remains complete or nearly complete. In ESRD subjects, gadopiclenol was effectively removed from the plasma after 1 hemodialysis session, and up to 3 hemodialysis sessions were sufficient to completely clear it. No safety concern was raised. Therefore, no dose adjustment seems necessary in this patient population.

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 …”

“…It is known that urinary excretion is the main route of elimination for gadopiclenol. In healthy adult volunteers, depending on study, 79.1% (±23.7) of the dose is eliminated via urine over 6 hours after injection 8 and 85.2% (±25.7) of the dose is eliminated within 48 hours 7 …”

“…It is known that urinary excretion is the main route of elimination for gadopiclenol. In healthy adult volunteers, depending on study, 79.1% (±23.7) of the dose is eliminated via urine over 6 hours after injection 8 and 85.2% (±25.7) of the dose is eliminated within 48 hours. 7 Efficacy results from this study showed that gadopiclenolenhanced MRI allowed the detection of 1 additional lesion in 2 patients from the CNS cohort.…”

“…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 ]. …”