Pharmacokinetics and safety of gadopiclenol in Japanese healthy volunteers

Abstract

Purpose: The aim of this study was to evaluate the pharmacokinetics and safety of gadopiclenol in Japanese healthy volunteers. A population-based pharmacokinetic approach was used to compare pharmacokinetic parameters with a non-Japanese adult population.

Materials and methods: In this double-blind, placebo-controlled phase I study, Japanese healthy volunteers were randomized to receive gadopiclenol (at 0.025, 0.05, or 0.1 mmol/kg) or a placebo. Blood and urine samples were collected up to 24- and 48-h post-administration, respectively. The pharmacokinetic profile of gadopiclenol was evaluated using standard non-compartmental analysis. Adverse events (AEs) were collected during the whole study period.

Results: Overall, 27 participants were randomized (median [range] age: 22 [20-43] years; 52% male): 18 received gadopiclenol (6 in each dose group), and 9 received the placebo. The mean systemic exposure of gadopiclenol increased proportionally with the injected dose (area under the curve [AUC]: 215-1034 μg/mL.h) and was comparable between the three dose groups when normalized to dose (AUC/dose: 182-189 μg/mL/g.h) and to non-Japanese (168-183 μg/mL.h). The mean terminal half-life (1.43-1.86 h), and the distribution volume (11.3-15.2 L) were also similar to those of non-Japanese healthy volunteers (1.50-1.73 h and 13.0-15.5 L, respectively). The mean fraction of gadopiclenol excreted in urine was between 87 and 95%, depending on the administered dose. Most of gadopiclenol (median of 95.7%) was excreted within 24 h after administration. The mean total clearance was comparable between the different administered doses (5.3-5.6 L/h) and similar to the mean renal clearance. No gadopiclenol-related AEs were reported.

Conclusions: The pharmacokinetic profile of gadopiclenol is similar in Japanese and non-Japanese healthy volunteers. The population pharmacokinetic analysis showed no significant ethnic disparities between these two populations and suggested that no dose adjustment was required for Japanese patients. Gadopiclenol had a very good tolerability in Japanese healthy volunteers with no adverse reactions reported.

Keywords: Gadopiclenol; Macrocyclic; Magnetic resonance imaging; Pharmacokinetics; Safety.

Fig. 1

Time course of the mean plasma concentration of gadopiclenol in Japanese healthy participants. Mean gadopiclenol plasma concentration after single ascending intravenous doses (0.025, 0.05, and 0.1 mmol/kg) of gadopiclenol over time. LOQ: limit of quantification (5 µg/mL)

Fig. 2

Pharmacokinetic parameters of gadopiclenol after intravenous administration in Japanese healthy participants. Box plot, representing the pharmacokinetics parameter of gadopiclenol administered as a single dose of 0.025, 0.05, or 0.1 mmol/kg: maximum plasma concentration measured (Cmax, µg/mL), area under the observed concentration–time curve from zero (time of drug administration) to infinite (AUC 0-inf, µg/mL.h, terminal elimination half-life of gadopiclenol (t1/2, h), volume of distribution (Vd, L), renal clearance (Clr, mL/min/kg), and percentage of gadopiclenol excreted in urine (fe, %). The arithmetic mean is represented by the cross and value, the median by the solid line, and the first and third quartile by the ends of the ‘Box’. The whiskers show the lowest data value still within 1.5 IQR (interquartile range). Data values that do not fall between the whiskers are plotted as outliers (markers outside of the whiskers). C_max peak concentration, AUC_0-inf area under the plasma concentration curve from injection to infinity, t_1/2 terminal half-life, Vd distribution volume, Clr renal clearance

Fig. 3

Simulated gadopiclenol plasma concentrations in Japanese and non-Japanese population. Box plot representation of simulated plasma concentration (mg/L) of gadopiclenol after a single intravenous injection at a dose of 0.025, 0.05, or 0.1 mmol/kg in Japanese and Non-Japanese populations with normal renal function. In the box plot, the median is represented by the solid line, and the first and third quartile by the ends of the “box”. The whiskers show the lowest value still within 1.5 interquartile range (IQR) of the lower quartile, and the highest value still within 1.5 IQR of the upper quartile

Fig. 4

Simulated total systemic exposure of gadopiclenol in Japanese and non-Japanese population. Box plot representation of simulated AUC inf (mg/L.h) of gadopiclenol after a single intravenous injection at a dose of 0.025, 0.05, or 0.1 mmol/kg in Japanese and Non-Japanese populations with normal renal function. The median is represented by the solid line, and the first and third quartile by the ends of the “box”. The whiskers show the lowest value still within 1.5 interquartile range (IQR) of the lower quartile, and the highest value still within 1.5 IQR of the upper quartile