Gadopiclenol

Gadopiclenol is a paramagnetic agent for Magnetic Resonance Imaging (MRI).

The contrast-enhancing effect is mediated by gadopiclenol which is a macrocyclic non-ionic complex of gadolinium, the active moiety which enhances the relaxation rates of water protons in its vicinity in the body, leading to an increase in signal intensity (brightness) of tissues.

When placed in a magnetic field (patient in MRI machine), gadopiclenol shortens the T₁ and T₂ relaxation times in targeted tissues. The extent to which a contrast agent can affect the relaxation rate of tissue water (1/T₁ or 1/T₂) is termed relaxivity (r₁ or r₂).

Gadopiclenol presents a high relaxivity in water due to its chemical structure, because it can exchange two water molecules, which are linked to the gadolinium to complete its coordination number in addition to the four nitrogens and the three oxygens of the carboxylate functions of the gadopiclenol chelate. This explains that, gadopiclenol given at half dose of gadolinium compared to other non-specific gadolinium-containing contrast agents, may provide the same contrast enhancement.

Relaxivity at 37°C for gadopiclenol:

Absorption

The absolute bioavailability of gadopiclenol (in humans) is 100%, as it is only administered via the intravenous route.

After an intravenous dose of 0.1 to 0.2 mL/kg BW (equivalent respectively to 0.05 and 0.1 mmol/kg BW), the C_max was 525 ± 70 mcg/mL and 992 ± 233 mcg/mL, respectively.

The C_max increased 1.1-fold, 1.1-fold and 1.4-fold and the AUC_inf increased 1.5-fold, 2.5-fold and 8.7-fold in patients with mild, moderate and severe renal impairment, respectively after a dose of 0.2 mL/kg BW (equivalent to 0.1 mmol/kg BW).

In addition, the increase in C_max and AUC_inf is expected to be similar with a dose of 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) based on the results of population pharmacokinetic simulations.

Distribution

After intravenous administration gadopiclenol is rapidly distributed in the extracellular fluids. After a dose of 0.1 ml/kg BW (equivalent to 0.05 mmol/kg BW) the distribution volume Vd was 12.9 ± 1.7 L.

The in vitro binding of 153Gd-gadopiclenol to human plasma proteins is negligible and independent of the gadopiclenol concentration, as 153Gd-gadopiclenol bound 0.0–1.8% to human plasma proteins and 0.0-0.1% to human red blood cells.

Biotransformation

Gadopiclenol is not metabolised.

The lack of metabolism is confirmed by in vitro data using pooled human liver microsomes incubated with 153Gd-gadopiclenol. After 120 minutes ≥ 95% of the 153Gd-gadopiclenol remained in unchanged form. The results were similar when heat inactivated pooled human liver microsomes (negative controls) were incubated with 153Gd-gadopiclenol, indicating that 153Gd-gadopiclenol is not metabolised.

Elimination

Gadopiclenol is eliminated rapidly in unchanged form through the kidneys by glomerular filtration. After a dose of 0.1 to 0.2 mL/kg BW (equivalent respectively to 0.05 and 0.1 mmol/kg BW), the mean plasma elimination half-life (t_1/2) in healthy volunteers with a normal renal function was1.5 and 1.7 hour, respectively, and the clearance was 100 ± 10 mL/min and 96 ± 12 mL/min, respectively. Urinary excretion is the major route of elimination of gadopiclenol, with approximately 98% of the dose excreted in urine after 48 hours regardless of the dose administered.

Linearity/non-linearity

The pharmacokinetic profile of gadopiclenol is linear in the studied dose range (0.05 to 0.6 mL/kg BW equivalent to 0.025 to 0.3 mmol/kg BW), without difference between males and females. Mean maximum concentration (C_max) and Area Under the Curve (AUC_inf) increased proportionally to the dose.

Paediatric population

One Phase II study (Study 3) with a single dose of gadopiclenol at 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) was conducted and included 60 paediatric patients aged 2 to 17 years old undergoing CNS MRI.

Individual parameters predicted from the population pharmacokinetic model and normalised by BW were similar between adults and children. The terminal half-life was 1.77 hour for age group 12-17 years old, 1.48 hour for age group 7-11 years old and 1.29 hour for age group 2-6 years old. The median clearance ranged from 0.08 L/h/kg (for age group 12-17 years old) to 0.12 l/h/kg (for age group 2-11 years old).

The pharmacokinetics of gadopiclenol in children aged 2 to 17 years are comparable to the pharmacokinetics in adults.

Renal impairment and dialysability

The elimination half-life (t_1/2) is prolonged in subjects with renal impairment, increasing with the degree of renal impairment. In patients with mild (60 ≤ eGFR < 90 mL/min), moderate (30 ≤ eGFR < 60 mL/min) and severe (15 ≤ eGFR < 30 mL/min) renal impairment, the mean t_1/2 was 3.3, 3.8 and 11.7 hours, respectively and the clearance was 1.02, 0.62 and 0.17 mL/min/kg, respectively.

The C_max increased 1.1-fold, 1.1-fold and 1.4-fold and the AUC_inf increased 1.5-fold, 2.5-fold and 8.7-fold in patients with mild, moderate and severe renal impairment, respectively after a dose of 0.2 mL/kg BW (equivalent to 0.1 mmol/kg BW).

In addition, the increase in C_max and AUC_inf is expected to be similar with a dose of 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW) based on the results of population pharmacokinetic simulations.

Urinary excretion is delayed with the progression of renal impairment level. In patients with mild or moderate renal impairment, more than 90% of the administered dose was recovered in the urine within 48 hours. In patients with severely impaired renal function about 84% of the administered dose was recovered in the urine within 5 days.

In patients with End Stage Renal Disease (ESRD), 4 hour haemodialysis effectively removed gadopiclenol from plasma as the percentage of decrease in blood concentrations was 95 to 98% at the end of the first haemodialysis session.

Weight

The effect of weight was investigated with population pharmacokinetic simulations of patients with a BW ranging from 40 kg to 150 kg receiving a gadopiclenol dose of 0.1 mL/kg BW (equivalent to 0.05 mmol/kg BW). The ratios of median AUC_inf of gadopiclenol between a typical healthy subject of 70 kg and subjects weighing 40 kg and 150 kg was 0.86 and 2.06, respectively. The ratios of the plasma concentrations 10, 20 and 30 minutes after administration between a typical healthy subject of 70 kg and subjects weighing 40 kg and 150 kg ranged from 0.93 to 1.26.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

Juvenile animal toxicity studies have not revealed any relevant findings.