This phase I, ascending dose, double-blind, randomized, placebo-controlled trial was conducted in a single center (Hakata Clinic, Fukuoka, Japan), between May and July 2021. The study was approved by an independent ethics committee, and written informed consent was obtained from each participant. The study was registered at https://jrct.niph.go.jp/ (registration n°: jRCT2071210029) and Clinicaltrials.gov (registration n°: NCT04906005).

Male or female Japanese healthy volunteers aged 20–60 years, with a body mass index (BMI) of 18–25 kg/m2 were included. A Japanese healthy volunteer was defined as being born in Japan and having both parents and four grandparents (maternal and paternal) who are ethnically Japanese and having Japanese lifestyle, including diet, as determined by participant’s verbal report. Good health status was determined by the investigator according to past medical history, clinical examination, including 12 lead ECG, vital signs (blood pressure, pulse rate, respiratory rate, and body temperature), and laboratory tests at screening and inclusion.

Participants were randomized and double-blindly administered with gadopiclenol (0.5 M solution) or placebo (0.9% sodium chloride solution). Three doses (0.025, 0.05, and 0.1 mmol/kg) were investigated. Nine participants were included in each dose group (27 participants in total): 6 received gadopiclenol and 3 received the placebo, as it was done in the phase I pharmacokinetics study conducted on non-Japanese healthy volunteers [7]. Dose escalation to the next dose group was only allowed if the clinical and biological safety of all participants from the previous dose group was acceptable.

Both products were administered as a single intravenous (IV) bolus injection at a rate of 2 mL/second followed by a saline flush using a power injector.

Participants were confined for one night before the inclusion visit and 2 days post-administration. A safety follow-up visit was performed 7 days after gadopiclenol or placebo administration.

The pharmacokinetic analysis was carried out with a non-compartmental method using Phoenix WinNonlin (Version 8.1; Pharsight Corporation, Mountain View, CA). The main calculated parameters were: area under the plasma concentration curve (AUC), plasma peak concentration (Cmax), terminal half-life (t1/2), volume of distribution (Vd), total clearance (CL), renal clearance (Clr), and gadopiclenol fraction excreted in urine (fe).

According to previous pharmacokinetic studies in non-Japanese (Caucasian) healthy volunteers, blood samples (6 mL) were drawn 30 min before, 2, 5, 10, 20, 30, and 45 min, and 1, 2, 4, 6, 8, 12, and 24 h after drug administration. Urine was collected 30 min before drug administration, and during the following time intervals: 0–6 h, 6–24 h, and 24–48 h after drug administration. For both blood and urine, an additional sample was collected during the follow-up safety visit. The determination of gadopiclenol concentration in plasma and urine was performed using a validated liquid chromatography with tandem mass spectrometric detection (LC–MS/MS) method, with a limit of quantification (LOQ) of 5 µg/mL. Gadopiclenol assay in plasma and urine and pharmacokinetic analysis were performed by Eurofins ADME-Bioanalyses (Vergèze, France).

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature), electrocardiography (ECG), biochemistry, hematology, urinalysis, and estimated Glomerular Filtration Rate (eGFR) assessments were performed before and up to 48 h after drug administration, and during the safety follow-up visit. The eGFR was calculated using the Japanese coefficient-modified CKD-EPI formula [16]. Adverse events (AEs) were collected during the whole study period and tolerance at the injection site was monitored over 24 h after injection.

Descriptive summaries were performed using SAS (Version 9.4, SAS Institute Inc., Cary, NC, USA). Summary statistics (Number, Mean, Standard Deviation [SD], Median, Minimum, and Maximum) were presented for quantitative variables, and absolute and relative frequencies were presented for categorical variables.

A population pharmacokinetics modeling was performed to assess the impact of ethnicity on gadopiclenol pharmacokinetics. This was achieved using a Nonlinear Mixed Effect Modeling (NONMEM) software (v.7.4, Icon plc, Dublin, Ireland). The base model of the population pharmacokinetic analysis was obtained by combining data from Japanese participants in this study and others (non-Japanese adults with normal and impaired renal function, and pediatric patients from 2 to 17 years) who received gadopiclenol from three studies [7, 8, 13]. The population pharmacokinetic model that was previously developed in non-Japanese subjects was used to evaluate if it was predictive of Japanese subjects. Models evaluation was performed via NONMEM objective function and standard diagnostic or goodness of fit plots (predicted vs. observed, weighted residuals vs. predicted, weighted residuals vs. time). The first-order conditional estimation (FOCE) with interaction method was used. The covariate model was obtained using a univariate screening followed by a backward deletion process and should result in an improved fit. Validation of pharmacokinetic models was performed using visual predictive checks (VPC).

After preliminary checks and obtaining the final model, pharmacokinetic parameters (central volume of distribution [V1], peripheral volume of distribution [V2], total clearance [Cl], and terminal t1/2) were derived for Japanese and non-Japanese adults with normal renal function. In addition, gadopiclenol concentrations at 10, 20, and 30 min after administration and AUC for the doses 0.025 mmol/kg, 0.05 mmol/kg, and 0.1 mmol/kg were simulated in these two populations. One thousand replicates of each subject were obtained for each dose to determine the distribution of C10, C20, C30, and AUC. These exposures variables were compared by ethnic groups using descriptive statistics (minimum, 2.5th percentile, median, 97.5th percentile, geometric mean, and CV) as well as graphically using box-plots.