AMBELVIST Solution for injection Ref.[116696] Active ingredients: Gadoquatrane

In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with:

• differences in proton density
• differences of the spin-lattice or longitudinal relaxation times (T₁).
• differences in the spin-spin or transverse relaxation time (T₂).

Gadoquatrane alters the T₁ and T₂ relaxation times in tissues in the magnetic field of an MRI scanner. The extent to which a contrast agent can affect the relaxation rate (1/T₁ or 1/T₂) of tissue water is termed relaxivity (r₁ or r₂).

The relaxivity (r1) of gadoquatrane is presented in Table 3.

Table 3. Relaxivity (r₁) of Gadoquatrane* in Human Plasma at 37°C:

^* Each molecule of gadoquatrane contains 4 chelated gadolinium ions [see Description (11)].

Cardiac Electrophysiology:

At 5 times the recommended dose of gadoquatrane, clinically significant QTc interval prolongation was not observed.

The peak plasma concentration (C_max) and area under the concentration time curve (AUC) of gadolinium (Gd) increased proportionally over a dose range from 0.0025 to 0.05 mmol/kg of gadoquatrane (0.25 to 5 times the recommended dose). At the recommended dose, the median (5^th, 95^th percentile) C_max and AUC_inf were 394 (249, 628) µmol Gd/L and 462 (315, 766) µmol Gd*h/L, respectively. The pharmacokinetic (PK) parameters of gadolinium by age group are shown in Table 4.

Table 4. Pharmacokinetic Parameters (Median, (5^th, 95^th Percentile)) of Gadolinium* by Age Group:

Abbreviations: N, number of subjects; eGFR, estimated glomerular filtration rate; AUC_inf, area under the plasma concentration-time curve from time zero extrapolated to infinity; CL/BW, clearance normalized by body weight; Vss/BW, volume of distribution at steady state normalized by body weight; t_1/2eff, effective half-life; C₁₀, plasma concentration at 10 minutes post-dose; C₂₀, plasma concentration at 20 minutes post-dose
^* at the recommended dose of gadoquatrane

Distribution

After intravenous administration, gadoquatrane is distributed from the vascular to the extracellular space.

The median (5^th, 95^th percentile) volume of distribution over body weight of gadolinium at steady state (Vss/BW) is 0.205 (0.157, 0.252) L/kg.

Plasma protein binding is <1%.

Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.4)]. It is unknown whether the recommended dose of AMBELVIST results in similar or different levels of gadolinium retention relative to those of other approved macrocyclic GBCAs at their recommended doses.

Elimination

The median (5^th, 95^th percentile) effective elimination half-life (t_{1/2, eff}) of gadolinium is 1.6 (1.2, 2.6) hours.

The median (5^th, 95^th percentile) total body clearance over body weight (CL/BW) is 0.087 (0.052, 0.13) L/h/kg.

Metabolism

Gadoquatrane is not metabolized.

Excretion

Gadoquatrane is mainly eliminated through the kidneys by glomerular filtration. On average, 91% (CV 13%) of the dose was excreted in the urine within 12 hours after intravenous administration. Extrarenal elimination is negligible; less than 1% of the dose was detectable in feces.

Specific Populations

No clinically significant differences in PK of gadolinium were observed based on age (geriatric vs. younger patients) or sex (male vs. female).

Pediatric Patients

The PK profile of gadolinium in pediatric patients is generally comparable to and within range of that observed in adults. See Table 4 for the PK parameters of gadolinium at the recommended dose of gadoquatrane by age.

Patients with Renal Impairment

Gadolinium distributes into the extracellular space and is mainly eliminated by the kidney. Gadolinium clearance decreased as the severity of renal impairment increased, leading to higher total drug exposure (AUC) and prolonged excretion time. Despite the effects on total exposure, early plasma concentrations of gadolinium were not affected by the subjects' level of renal function [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

Table 5 presents the pharmacokinetic parameters of gadolinium at the recommended dose of gadoquatrane in adults with varying degrees of renal function (normal, mild, and moderate impairment) and for virtual patients representing severe renal impairment.

Table 5. Pharmacokinetic Parameters (Median, (5^th, 95^th Percentile)) of Gadolinium* by Renal Function in Adults:

Abbreviations: N, number of subjects; AUC_inf, area under the plasma concentration-time curve from time zero extrapolated to infinity; Vss/BW, volume of distribution at steady state normalized by body weight; CL/BW, clearance normalized by body weight; t_1/2eff, effective half-life; C₁₀, plasma concentration at 10 minutes post-dose; C₂₀, plasma concentration at 20 minutes post-dose
^* at the recommended dose of gadoquatrane
^† predicted based on virtual patients (N=10,000)

In patients with mild or moderate renal impairment, about 90% of the administered gadoquatrane was recovered in urine within 24 hours. In patients with severely impaired renal function, recovery of a similar amount is anticipated in urine within 5 to 7 days.

Gadoquatrane has been shown to be dialyzable in an in vitro hemodialysis study. After 1 hour of in vitro hemodialysis, approximately 97% of gadoquatrane was removed from the plasma.

Carcinogenicity

Carcinogenicity studies in animals have not been conducted with gadoquatrane.

Mutagenesis

Gadoquatrane was not mutagenic or clastogenic with or without metabolic activation in five strains of the Ames bacterial mutagenicity assay (TA100, TA98, TA1535, TA1537, and TA102), or in vitro and in vivo micronucleus assays.

Impairment of Fertility

No adverse effects on reproductive performance or pregnancy outcome were observed in parental rats following daily intravenous administration of gadoquatrane before and during gestation at up to 0.54 mmol Gd/kg/day (corresponding to 4 times the human exposure). At 1.54 mmol Gd/kg/day (12 times the human exposure), a slight increase in the number of dead embryos and the percentage of post-implantation loss (4 of the 20 females in the treatment group each having at least 3 dead embryos) was observed and considered potentially related to gadoquatrane.

14.1 Overview of Clinical Studies

The safety and effectiveness of AMBELVIST were investigated in two randomized, multicenter, double-blind, active comparator, crossover studies, Study 1 (NCT05915702) and Study 2 (NCT05915728). Study 1 focused on central nervous system (CNS) pathologies, while Study 2 addressed pathologies in non-CNS body regions.

In a random order separated by a 2- to 14-day period, each patient received AMBELVIST and an active comparator. AMBELVIST was administered at a dose of 0.01 mmol/kg, which delivers 0.04 mmol gadolinium (Gd)/kg. The active comparator was a macrocyclic GBCA (gadobutrol, gadoterate, or gadoteridol) administered at a standard dose of 0.1 mmol Gd/kg.

For each drug, pre-contrast (unenhanced) and paired (pre-contrast and post-contrast) image sets were separately evaluated by three independent central readers who were blinded to clinical information and identity of the contrast agent. Each reader assessed up to five lesions per patient on three visualization scores: contrast enhancement (4-point scale), delineation (4-point scale), and morphology (3-point scale). The number of lesions was also analyzed. An additional independent central reader performed lesion tracking to allow matching of lesions between pre-contrast and paired images.

14.2 MRI of the CNS

Study 1 included 305 patients scheduled for MRI with known or suspected pathology of the CNS. Of these, 237 patients had assessable MR image sets and at least one matching lesion between paired AMBELVIST and pre-contrast MRI. These patients had a mean age of 56 years (range: 20 to 84 years), with 58% being female. Of the study population, 67% were White, 29% Asian, 1% Black or African American, <1% of multiple racial background, and 3% of unspecified race.

The blinded readers' scores of paired pre- and post-AMBELVIST images and pre-contrast images alone for all lesion visualization criteria are presented in Table 6.

Table 6: Patient-Level CNS Visualization Scores Comparing Paired Pre- and Post-AMBELVIST to Pre-AMBELVIST MRI (N=237):

Abbreviations: CI, confidence interval; MRI, magnetic resonance imaging; SE, standard error
Notes: The average lesion score per patient was used. Contrast enhancement and border delineation were measured on a 4-point scale and internal morphology was measured on a 3-point scale. Only patients with at least 1 matched lesion were included in the analysis. Among them, for patients who had unmatched lesions between image sets, the missing scores were assigned the worst score of '1'. For each patient, difference at patient level was calculated as paired pre- and post-AMBELVIST average lesion score minus pre-AMBELVIST average lesion score; the reported mean difference was obtained by taking the average of these difference scores across patients.
^* p-value <0.0001 for all rows

AMBELVIST visualization scores and number of lesions identified per patient were similar to those of other tested GBCAs in descriptive analyses.

14.3 MRI of Non-CNS Body Regions

Study 2 included 410 patients with known or suspected pathology in non-CNS body regions, including head and neck, thorax, abdomen, pelvis, and extremities. Of these, 312 patients had assessable MR image sets and at least one matching lesion between paired AMBELVIST and pre-contrast MRI. These patients had a mean age of 58 years (range: 20 to 84), with 48% being female. Of the study population, 70% were White, 28% Asian, <1% Black or African American, and 2% of unspecified race.

A total of nine readers were divided into three specialization groups of three readers each for breast (N=32), cardiovascular (N=24), and other non-CNS body (N=256) imaging.

AMBELVIST demonstrated similar increases in lesion visualization scores across different reader groups (breast, cardiovascular, and other non-CNS body). Within the other non-CNS body group, scores also increased consistently across different anatomic regions. Lesion visualization scores for other non-CNS body imaging are summarized in Table 7.

Table 7. Patient-Level Body Lesion Visualization Scores Comparing Paired Pre- and Post-AMBELVIST to Pre-AMBELVIST MRI (N=256):

Abbreviations: CI, Confidence interval; MRI, magnetic resonance imaging; SE, Standard error
Notes: These data are based on 256 patients who had non-breast and non-cardiovascular body MRI. The average lesion score per patient was used. Only patients with at least 1 matched lesion were included in the analysis. Among them, for patients who had unmatched lesions between image sets, the missing scores were assigned the worst score of '1'. Contrast enhancement and border delineation were measured on a 4-point scale and internal morphology was measured on a 3-point scale. For each patient, difference was calculated as paired pre- and post-AMBELVIST average lesion score minus pre-AMBELVIST average lesion score; the reported mean difference was obtained by taking the average of these difference scores across patients.

AMBELVIST visualization scores and number of lesions identified per patient were similar to those of other tested GBCAs in descriptive analyses.