Safety and Gadolinium Distribution of the New High-Relaxivity Gadolinium Chelate Gadopiclenol in a Rat Model of Severe Renal Failure : Investigative Radiology

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Original Articles

Safety and Gadolinium Distribution of the New High-Relaxivity Gadolinium Chelate Gadopiclenol in a Rat Model of Severe Renal Failure

Fretellier, Nathalie PhD; Rasschaert, Marlène PhD; Bocanegra, Julien MS; Robert, Philippe PhD; Factor, Cécile PhD; Seron, Aymeric PhD; Idée, Jean-Marc PharmD; Corot, Claire PharmD, PhD

Author Information
doi: 10.1097/RLI.0000000000000793

Abstract

Until 2006, gadolinium-based contrast agents (GBCAs) were almost universally acknowledged as being among the safest drugs ever marketed.1 Since then, however, the class of drugs has been faced with 2 serious issues: first, the occurrence of nephrogenic systemic fibrosis (NSF), a highly debilitating disease observed in patients with severe acute kidney injury or advanced stages of chronic kidney disease (CKD).2 Then, in late 2013, progressive T1-weighted (T1w) signal hyperintensity was identified in specific brain regions on unenhanced T1w images, both in adults3 and pediatric populations4 (although no causal relationship has been demonstrated so far among repeated administration of GBCAs, brain T1 hypersignals, and any neurological toxicity5), making the public and clinicians more guarded with regard to the these agents in general.6 It should be noted that, in the majority of cases, NSF and T1w signal hyperintensities were observed in patients who had received a GBCA whose molecular structure included a linear polyamino-polycarboxylic ligand.7–10 On both occasions, health authorities worldwide implemented precautionary measures. For example, in Europe, this led to the withdrawal of the market authorizations of linear GBCAs in 2017 except for specific indications (liver or joint imaging).11 As a consequence of the NSF outbreak, linear GBCAs were contraindicated in patients with an estimated glomerular filtration rate under 30 mL/min/1.73 m2 and screening of kidney function was recommended. These mitigation strategies resulted in the almost complete elimination of the disease after 2009, although possible underreporting of unconfounded cases obviously cannot be ruled out.12,13

Nevertheless, the fact remains that the administration of GBCAs has undisputable benefits in many clinical indications.14 It is likely that the next generation of contrast agents for MRI will still include GBCAs.15,16 Recently, gadopiclenol, a new macrocyclic GBCA that exhibits high relaxivity and high kinetic inertness17 entered into clinical development.18–20 The high r1 relaxivity properties of this agent support its potential use at lower doses than currently available GBCAs, allowing equivalent visualization and diagnosis.17 Use of this contrast agent could be particularly interesting for the detection of small brain metastases, allowing the possible recourse to potentially significant therapeutic options including stereotactic radiosurgery or whole-brain radiation surgery.21

Consistent with the International Conference on Harmonization M3 guidelines,22 health authorities require that a comprehensive list of nonclinical studies be conducted for an in-depth investigation of the safety profile of any new drug candidate, including contrast agents. In addition to these mandatory regulatory studies, it seemed wise to investigate the toxicological profile of this new GBCA, compared with other GBCAs, in a sensitized and clinically translational experimental model such as severe renal insufficiency. Renally impaired patients are a highly vulnerable population with regard to the Gd retention and the risk of NSF. Therefore, although gadopiclenol is a macrocyclic GBCA, it seemed useful to study its safety in a preclinical model mimicking an at-risk clinical condition. The aim of this study was therefore to compare the safety profiles of gadopiclenol with other GBCAs of both linear and macrocyclic structures in a preclinical model of severe renal impairment. Particular attention was paid to the risk of NSF and tissue elemental Gd concentrations.

MATERIALS AND METHODS

All protocols were approved by the in-house Animal Welfare Ethics Committee. All experimental procedures were performed in accordance with French regulations and in strict compliance with the European Economic Community Directive (2010/63/EU) on animal welfare. All experiments (administrations, clinical and histological examinations, and total Gd concentration measurements) were carried out blindly. Animals were randomized.

Study Design

A total of 40 male Wistar rats (Centre d'Elevage René Janvier, Le Genest-Saint-Isle, France) were acclimatized for 10 days with ad libitum access to water and food (A04; SAFE, Augy, France) before starting the experiments. Renal failure was induced by placing the animals on 0.75% wt/wt adenine-enriched diet23 for 21 days (starting on day −7). Rats were randomly allocated (n = 8/group) to daily intravenous injections of 2.5 mmol/kg of gadopiclenol (0.5 M; synthetized by Guerbet, Villepinte, France), gadoterate meglumine (Dotarem, 0.5 M; Guerbet, Villepinte, France), gadodiamide (Omniscan, 0.5 M; GE Healthcare, Chalfont St Giles, United Kingdom), gadobutrol (Gadovist, 1 M; Bayer Healthcare, Berlin, Germany; diluted 2-fold in saline), or iso-osmolar saline (5 mL/kg) for 5 consecutive days starting on day 0, 1 week after starting the adenine diet. The 3 control GBCAs were from commercial formulations. Skin biopsies were taken from the backs of animals under isoflurane anesthesia for subsequent analysis on day 0 (5 minutes after the first administration) and day 14. The rats were euthanatized on day 25 (ie, 3 weeks after the last administration) by exsanguination under 5% isoflurane.

The study schedule is summarized in Figure 1.

F1
FIGURE 1:
Experimental design. Adenine-containing diet (0.75%) was administered for 3 weeks, that is, 21 days (orange bar). Starting on day 0, rats received 5 consecutive daily intravenous injections of saline or of a gadolinium-based contrast agent (green arrows) (2.5 mmol/kg/administration) from day 0 to day 4. The animals were euthanatized 3 weeks after the administration period (day 25).

Selected tissues (liver, spleen, left kidney, heart, dorsal skin, femoral epiphysis, brain, cerebellum, plasma) were frozen (−20°C) and then assayed for elemental (total) gadolinium (Gd) (see Bioanalysis section). Dorsal skin samples were fixed in 10% neutral formalin and preserved for subsequent histopathological examinations (see Histopathology section).

Clinical follow-up, including checking for behavioral abnormalities, was performed on a daily basis. The clinical status of the rats was also measured using a dedicated clinical scale twice per week. This scale required the examination of the skin lesions, hair growth, and appearance of the hair, as well as the monitoring of the presence or absence of a cutaneous wrinkling (indicating dehydration). The clinical score is detailed in Table 1. Body weight was measured twice per week (except during the administration week when it was measured once a day).

TABLE 1 - Dedicated Clinical Scale
Criteria Description of Observation Score
Type of lesions No lesion 0
Healed 2
Crusted 4
Open wound 6
Form of lesions Isolated 1
Punctiform 2
Grouped 3
Location of lesions Back, abdomen, or flank 1
2 regions 2
No. lesions Below 5 lesions 2
Low 4
Moderate 6
Severe 8
Hair growth Normal 0
Partial 1
None 2
Appearance of hair Normal 0
Abnormal 1
Cutaneous wrinkling Absence 0
Presence: low 1
Presence: severe 2

Biochemistry

Plasma levels of total calcium, phosphorus, and transferrin-bound iron (Fe) (Vitros II Autoanalyzer; Ortho Clinical Diagnostics, Raritan, NJ) were measured as well as plasma levels of alanine transaminase, aspartate transaminase, total bilirubin, total proteins, albumin, alkaline phosphatases, cholesterol, creatinine kinase, globulins, creatinine, and urea (MScan II Automat; Melet Schloesing, Osny, France). These analyses were performed on day −7 (ie, 1 week before the start of the injections), day 2, day 14, and day 25. Creatinine clearance from a 24-hour urine collection was also determined on day −3 (ie, 3 days before the start of injections), day 11, and day 25, using the standard formula: creatinineurine × diuresis/creatinineplasma and corrected for body weight. Blood samples were taken from the sublingual vein. All assays were performed in duplicate.

Skin Histopathology

Histological studies were performed in blinded conditions by a board-certified pathologist (Atlantic Bone Screen, St Herblain, France). After fixation of the tissues in 10% neutral buffered formalin, they were embedded in paraffin and then sectioned (4 μm thick). Three types of examinations were performed on the dorsal skin sections to detect signs of fibrosis: (a) histological description of the hematoxylin-eosin–stained tissue sections with semiquantitative evaluation (scoring system: 0, normal; 1, minimal; 2, mild; 3, moderate; 4, marked; and 5, severe) of elementary findings (dermal inflammation, fibroblasts density, fibroblastic activation, subepidermal fibroplasia, acanthosis, necrosis/ulceration, dermal collagen aspect); (b) histomorphometric analysis of fibrosis identified by picrosirius red staining; and (c) quantitative analyses (epidermal and dermal thickness, dermal cellularity) with Nikon Nis-D (Nikon Instruments Europe, Amsterdam, the Netherlands) or NDP View 2 (Hamamatsu Photonics, Massy, France) softwares.

The histopathological analyses were performed on dorsal skin samples biopsied at day 14 and day 25 (ie, euthanasia).

Electron Microscopy Analysis

Skin biopsies (for the gadobutrol, gadopiclenol, and gadodiamide groups) were taken during the euthanasia process and fixed in Karnovsky solution. The material was then subdivided into smaller pieces (approximately 2 mm3), postfixed in 1% osmium tetroxide, routinely processed (automated tissue processor Lynx/Leica), and embedded in Epon resin (EMBed812) blocks.

Semithin sections (0.8 μm, double toluidine blue/basic Fuchsin staining) were prepared from all blocks and evaluated by light microscopy for orientation and trimming of the tissue area for electron microscopy. Selected blocks (2 per animal, 2 animals per group) were sectioned into ultrathin sections (80 nm, contrasted with uranyl and lead salt solutions), and then the grids with the representative sections were blinded (dosage groups) examined by electron-filtering transmission electron microscopy (TEM) (Zeiss LEO 912 AB, Oberkochen, Germany). Elemental analysis was performed by the electron energy loss spectroscopy (EELS) method. All digital images were captured with a 2000 × 2000-pixel side-entry CCD camera.

Doubtful areas for each section were examined by EELS for Gd and Fe content. Inclusions with a distinct Gd signal were also analyzed for oxygen (O) and phosphorus (P) content (iTEM software package; OSIS, Münster, Germany).

Determination of Elemental Gadolinium Concentration

Elemental Gd was assayed in the plasma, urine, feces, spleen, heart, brain (cerebral cortex), cerebellum, dorsal skin, liver (1 sample from the left lobe), left kidney, and left femur (both epiphyses) by inductively coupled plasma mass spectrometry (ICP-MS) using an ELAN DRC Plus (PerkinElmer Life and Analytical Sciences, Inc, Waltham, MA) after sample mineralization in 65% nitric acid for 8 hours at a temperature of 80°C. The lower limit of quantification in diluted mineralized solutions was 0.05 μg/L.

Relaxometry

Relaxometry in the dorsal skin (day 0, day 14, and day 25), liver, and femur epiphysis samples (day 25) was measured as described elsewhere23 (operating at a proton frequency of 60 MHz (ie, 1.42 T) and at the temperature of 37°C ± 2°C. Samples were diluted (1:11 for the skin, 1:6 for the liver and bone samples) in a 90:10 solution of D2O/H2O before mashing. D2O was used to increase relaxation time and thus to increase sensibility of the relaxometry technique.

Skin was ground with a Precellys homogenizer (Bertin Technologies, Montigny-le-Bretonneux, France). Bone was first immersed in a liquid nitrogen bath (−196°C), and a first grinding step was then performed in an Ultra-Turrax homogenizer (IMLAB, Lille, France), and a second grinding step was performed with a Precellys homogenizer. Liver samples were ground with a GentleMacs Dissociator (Miltenyi Biotec, Paris, France).

Before measurement, the suspension was mixed to avoid sedimentation, then checked visually to ensure a homogeneous appearance.

The standard sequence of the Minispec (Bruker BioSpin MRI GmbH, Ettlingen, Germany) was a 2-pulse inversion recovery spin echo with a fixed relaxation delay of 5 × T1. Total Gd was then determined in samples by ICP-MS (see Bioanalysis section).

The relaxivity (r1 values) of each tissue sample was determined as described previously in other publications24 by spiking the tissue homogenate (skin, liver, and femur epiphyses) from nontreated rats with the GBCAs and calculated according to the following formula: r1 = (1/T1sample − 1/T1diamagnetic)/[Gd] sample, with relaxation rate (1/T1) expressed in s−1, Gd concentration in mM, and r1 relaxivity in mM−1·s−1.

When the 1/T1 − 1/T1diamagnetic value was less than 20% of the 1/T1diamagnetic value in the absence of visually assessed Gd precipitation (ie, because of a low total Gd concentration in the sample), r1 relaxivity was considered to be not measurable. For a same group, when less than 4 samples were measurable, the mean and SD were not determined, and “ND” was indicated on the graphs.

Statistical Analysis

Data are expressed as mean ± standard deviation (SD). Outliers for all data were identified and excluded from the analysis according to the ROUT (“Robust Regression and Outlier Removal”) method (1% risk).24

For each study, the Shapiro-Wilk test was used to assess the normality of the distribution of the data in each group. In all groups, data with homogeneous variances and a normal distribution were analyzed using 1-way analysis of variance (ANOVA) or 2-way ANOVA followed by Dunnett test, Bonferroni test, or Tukey test for multiple comparisons when the ANOVA was significant. Data showing nonhomogeneous variances or a nonnormal distribution were analyzed using the Kruskal-Wallis test followed by Dunn test when the Kruskal-Wallis test was found to be significant.

For calculation of the means, SDs, and for statistical tests on Gd levels in tissues, values below the lower limit of quantification were arbitrarily replaced by zero. Statistics regarding Gd concentrations in tissues were performed without the control group that received no Gd to compare only the GBCAs.

The ex vivo relaxivity r1 values were compared using Student t test. The 95% confidence intervals (CIs) for the ex vivo r1 relaxivity mean were calculated (mean ± 2 standard error of the mean) and compared with the in vitro r1 relaxivity values ±23% (in vitro r1 range). If the CI for the in vivo relaxivity r1 mean was found to be fully included in the in vitro r1 relaxivity range, the ex vivo Gd form was hypothesized to be equivalent to the in vitro Gd form (ie, chelated, dissociated, or precipitated, according to the respective r1 relaxivity value), or otherwise different.23

Statistical analyses were carried out using GraphPad Prism software (GraphPad Software Inc, San Diego, CA). A P value of 0.05 or less was considered to indicate a significant difference.

RESULTS

Clinical Signs

A dramatic decrease in body weight was observed in all groups over the adenine diet period (Fig. 2). No statistical difference between the test groups was observed.

F2
FIGURE 2:
Body weight (mean + SD) of rats repeatedly treated with intravenous gadopiclenol, gadoterate, gadobutrol, gadiodiamide, or saline and placed on a 0.75% wt/wt adenine-enriched diet (day −7 until day 14). The bar indicates the period with the adenine-enriched diet. Two gadodiamide-treated rats were euthanatized (day 14 and day 17) and were therefore excluded for mean calculation in the gadodiamide group.

No behavioral or other clinical abnormalities were observed in the gadopiclenol, gadoterate, and gadobutrol groups when compared with the saline control group. Similarly, no macroscopic skin lesions were observed in the rats treated with gadopiclenol, gadoterate, gadobutrol, and saline. However, skin lesions (found on both the back and abdomen) were observed in all 8 gadodiamide-treated rats (ulcerations, scabs, wrinkled skin), as well as chromodacryorrhea, piloerection, and dull coat, as demonstrated by a progressive increase in the cumulated clinical score (Fig. 3). The lesions were first observed on day 4, that is, the day of the last injection. Spontaneous regression of some lesions was observed in only 1 animal with complete disappearance at study completion. Two gadodiamide-treated rats were euthanatized for ethical reasons (day 14 and day 17, ie, 10 and 13 days after the last gadodiamide administration) because of severe skin lesions and clinical signs (low or no activity, prostration, severe dehydration, lower body weight gain).

F3
FIGURE 3:
Clinical score (mean + SD) based on a dedicated clinical scale used throughout the study in renally impaired rats repeatedly treated with intravenous gadopiclenol, gadoterate, gadobutrol, or saline.

Skin Histopathology

In the gadodiamide-treated group, qualitative and semiquantitative histologic analyses revealed a pathological pattern including dermal inflammatory lesions, acanthosis, fibroblastic densification with either diffuse or localized (subepidermal) fibroblastic activation, and epidermal necrosis (ulcerations and serocellular scabs) (Table 2). The presence of granular and basophilic deposits, pyknosis, caryolysis of dermal fibroblasts, and fragmentation of dermal collagen fibers was interpreted as dermal necrosis in the gadodiamide-treated group. On day 14, the animals presented with mostly epidermal ulcerative lesions and adjacent dermal necrosis (Fig. 4), whereas on day 25, they presented mostly high-intensity acanthosis and fibroblastic densification. No skin lesions were evidenced in the groups treated with saline, gadopiclenol, gadoterate, and gadobutrol, regardless of the time point.

TABLE 2 - Scoring (Mean ± SD) and Percentage of Incidence Among the Groups (Between Parentheses) of Different Histological Observations
Day of Sampling Group Inflammation Acanthosis Fibroblast Activation Subepidermic Fibroplasia Fibroblastic Density
(0–5) (0–5) (0–5) (0–5) (0–4)
Day 14 Saline 0.3 ± 0.5 (0%)* 0.1 ± 0.4 (13%) 0.1 ± 0.4 (13%)** 0.1 ± 0.4 (0%) 0.3 ± 0.5 (25%)**
Gadoterate 0.1 ± 0.4 (0%)** 0.3 ± 0.5 (25%) 0.0 ± 0.0 (0%)*** 0.0 ± 0.0 (0%)* 0.0 ± 0.0 (0%)***
Gadobutrol 0.1 ± 0.4 (0%)** 0.3 ± 0.5 (25%) 0.0 ± 0.0 (0%)*** 0.0 ± 0.0 (0%)* 0.0 ± 0.0 (0%)***
Gadopiclenol 0.5 ± 0.5 (0%) 0.1 ± 0.4 (13%) 0.3 ± 0.7 (13%)** 0.1 ± 0.4 (0%) 0.0 ± 0.0 (0%)***
Gadodiamide 2.1 ± 1.4 (63%) 2.0 ± 1.3 (86%) 1.3 ± 1.0 (86%) 0.5 ± 0.5 (0%) 2.9 ± 1.1 (100%)
Day 25 Saline 0.1 ± 0.4 (0%)*** 0.1 ± 0.4 (13%)*** 0.9 ± 0.6 (75%) 0.1 ± 0.4 (0%) 0.6 ± 0.5 (63%)**
Gadoterate 0.3 ± 0.5 (0%)** 0.1 ± 0.4 (13%)*** 1.1 ± 0.6 (88%) 0.1 ± 0.4 (0%) 1.4 ± 0.7 (88%)
Gadobutrol 0.4 ± 0.7 (13%)** 0.8 ± 0.9 (50%)* 0.6 ± 0.7 (50%)* 0.0 ± 0.0 (0%)* 0.9 ± 1.1 (50%)**
Gadopiclenol 0.3 ± 0.5 (0%)** 0.5 ± 0.8 (38%)** 0.6 ± 0.5 (63%)* 0.3 ± 0.5 (0%) 0.8 ± 0.7 (63%)**
Gadodiamide 2.3 ± 0.8 (83%) 3.7 ± 0.5 (100%) 2.0 ± 0.9 (100%) 1.5 ± 1.4 (50%) 3.8 ± 0.8 (100%)
All the statistics indicated are with respect to the gadodiamide group (*P < 0.05; **P < 0.01; ***P < 0.001).

F4
FIGURE 4:
Typical ulcerative changes in the epidermis of a rat treated with gadodiamide (A) compared with renally impaired rat treated with gadopiclenol (B). Hematoxylin and eosin staining, ×20.

Quantitative analysis revealed a significantly higher density of fibroblasts in the case of gadodiamide-treated rats at both time points compared with the saline controls, unlike in the animals treated with the 3 macrocyclic GBCAs (Fig. 5). No between-group differences in the dermal and hypodermal thickness were observed (data not shown).

F5
FIGURE 5:
Quantitative analysis: number of fibroblasts/mm2 in the dermis (mean + SD) of renally impaired rats repeatedly treated with intravenous gadopiclenol, gadoterate, gadobutrol, or saline (blinded measurement using Nikon Nis-D software).

Transmission Electron Microscopy

Ultrastructural examination of the sections of the 2 representative skin biopsies from each animal revealed that the epidermis and dermis were normal, with compact collagen fibers and numerous interspersed fibroblasts, some macrophages, and mast cells.

A striking observation was made in the gadodiamide group, that is, numerous dark deposits were observed on collagen and in some cells. At higher magnification, the dark deposits on longitudinal (Fig. 6E) and transversal (Fig. 6F) collagen fiber sections displayed a filamentous fiber incrustation with a “halo” formation. Analysis by EELS revealed the presence of Gd (Fig. 6F). In the fibroblasts, multiple membrane-bound dark inclusions with mostly filamentous texture with positive Gd, O, P signals, and a negative Fe signal were noted in the gadodiamide group only (Fig. 6G). Some of them were longitudinally shaped, resembling oblique sectioned Gd/incrusted collagen fibers. The few identified macrophages profiles showed some dark lysosomal inclusions with sparsely positive Gd content. The observed mast cells displayed common secretory granules only (Fig. 6H).

F6
FIGURE 6:
A, Overview of the normal organization of collagen fibers in transversal section, and a circulating fibroblast with a normal ultrastructure, gadopiclenol group. B, Dark lysosomal inclusions with a weak Gd signal, in cell fragments, probably a damaged macrophage, gadobutrol group. C and D, Gd-positive dark lysosomal inclusions in a macrophages, gadopiclenol group. E and F, Filamentous, Gd-positive incrustation on collagen fibers, in longitudinal (E) and transversal (F) sections, gadodiamide group. G, Gd-positive membrane-bound dark inclusion (identified as a lysosome) in a fibroblast, gadodiamide group. H, Gd-positive lysosomal inclusions in a macrophage, gadodiamide group.

In the gadobutrol and gadopiclenol groups, no dark deposits were found on the collagen fibers. The examined fibroblasts displayed a normal ultrastructure, and no dark inclusions with Gd content were detected (Fig. 6A). The mast cells only displayed common secretory granules. However, some cell fragments were found (probably damaged macrophages) with numerous dark lysosomal inclusions showing a positive Gd signal (Fig. 6B) between the collagen bundles of 1 gadobutrol sample. In the gadopiclenol samples, all identified macrophages showed a number of dark lysosomal inclusions with a positive Gd content (Fig. 6C, D). In both groups, the Gd deposits had a similar rough-textured appearance.

A summary of the observations found during rat skin samples examination by TEM appears in Table 3.

TABLE 3 - Summary of the Observations Found During Examination of the Rat Skin Samples by Transmission Electron Microscopy
Group Rat # Dark Deposits With Positive Gadolinium Signal
Collagen Fibroblasts Lysosomes of Macrophages or Cell Fragments
Gadobutrol #41 Not evidenced Not evidenced Yes
#46 Not evidenced Not evidenced Not evidenced
Gadopiclenol #1 Not evidenced Not evidenced Yes
#3 Not evidenced Not evidenced Yes
Gadodiamide #12 Yes Yes Not evidenced
#30 Yes Yes Yes

Biochemistry

The adenine-enriched diet was associated with a dramatic decrease in creatinine clearance on day 11 compared with day −3, in all groups (overall mean of 0.55 ± 0.25 on day −3 compared with 0.12 ± 0.04 mL/min/100 g body weight on day 11, P < 0.001). This effect was still obvious at day 25 (0.17 ± 0.07 mL/min/100 g body weight, not significant vs day 11). The GBCAs did not affect the creatinine clearance, regardless of the considered time point (Fig. 7).

F7
FIGURE 7:
Creatinine clearance (mean + SD) determined before the start of gadolinium-based contrast agent administrations (day −3) and at 11 days (day 11) or 25 days (day 25) after first administration.

No treatment-related effect on plasma levels of transaminases, alkaline phosphatase, total proteins, glucose, calcium, phosphorus, urea, uric acid, triglycerides, creatine kinase, globulins, and total bilirubin was observed, regardless the group (Supplemental Digital Content, https://links.lww.com/RLI/A627). However, the adenine-enriched diet was associated with a progressive increase in plasma urea, creatinine, phosphorus, and conversely, a gradual decrease in plasma iron and phosphatase alkaline levels until the end of the adenine period (day 14).

Elemental Gadolinium Concentrations

Elemental Gd concentrations in all tissues appear in Figure 8. Elemental Gd concentrations determined in the skin samples 10 days after the last injection (day 14) were found to be similar in the gadopiclenol, gadoterate, and gadobutrol groups, whereas in the gadodiamide-treated group, it was increased by a factor of 8.5 to 10 (P < 0.01). At the end of the study (day 25), Gd concentrations had decreased in all groups, showing a washout of −83% ± 11% between days 14 and 25 for the gadoterate and gadobutrol groups, and of −54% ± 34% for the gadopiclenol group. The concentrations in the gadopiclenol group at this later time point were therefore slightly higher, but far lower compared with those of the gadodiamide group (−38% ± 25%). No significant difference in elemental Gd concentrations measured in the skin was observed for 3 macrocyclic GBCAs, regardless of the time point.

F8
FIGURE 8:
Elemental Gd concentrations determined by ICP-MS (mean ± SD and individual values) in various tissues at euthanasia (day 25) (skin: days 0, 14, and 25; urine and feces: days 11 and 25).

The kidney parenchyma showed the highest Gd concentrations that were in the same range for all groups (not significant) 3 weeks after the injection period. Gd concentrations in the heart were also similar between all groups.

In the liver parenchyma, elemental Gd concentrations after the gadopiclenol injections were similar to those after the gadodiamide injections, and higher than those measured in the gadoterate and gadobutrol groups (P < 0.05).

In the spleen, femur epiphyses, and the central nervous system, Gd concentrations after the gadopiclenol injections were in the same range as after the gadoterate and gadobutrol injections (slightly lower in the cerebral cortex), and significantly lower than those after the gadodiamide injections (P < 0.01 in the cerebral cortex, P < 0.001 in the cerebellum and femur, not significant in the spleen for gadopiclenol).

In the urine and feces, no differences were noted on day 11, although Gd in the feces of the gadodiamide group was slightly decreased. On day 25, 3 weeks after the last injection, Gd was still being eliminated in the urine and feces, but at lower concentrations.

Relaxometry

Skin

On day 0 (5 minutes after the first administration), the 95% CI of the r1 relaxivity mean was within the in vitro reference range for all the GBCA groups. Conversely, for gadodiamide, on day 14 and day 25, the 95% CI of the r1 mean was significantly increased and above the reference in vitro range (Fig. 9A). In the case of gadoterate, on days 14 and 25, the r1 relaxivity values were either within the in vitro range (1 rat) or not computable (1/T1 − 1/T1diamagnetic values less than 20% of the 1/T1diamagnetic value). For gadobutrol, on days 14 and 25, the r1 values were not computable. For gadopiclenol on day 14, the r1 mean value was included in the in vitro range, but 3 individual values were higher than the in vitro range (high variability). On day 25, the r1 means were not computable for the 3 macrocyclic GBCAs, because the Gd concentrations in the skin were too low.

Liver

The 95% CI of the r1 relaxivity values measured in the liver samples (day 25) from the gadodiamide group was much higher than the in vitro reference range. In the gadoterate and gadobutrol groups, the r1 relaxivity values were not determined since all the [Gd]total values were below the LOQ in this group (ie, the 1/T1 − 1/T1diamagnetic values were less than 20% of the 1/T1diamagnetic value). The 95% CI of the r1 relaxivity mean in the gadopiclenol group was almost entirely within the in vitro reference range, except for a single r1 value (Fig. 9B).

F9
FIGURE 9:
Ex vivo r1 relaxivity (95% incidence interval and individual values) in the skin (A) on days 0, 14, and 25; in the liver (B) on day 25 and in femur (C) samples on day 25. The color bars correspond to the in vitro r1 range of each product in the matrix. ND, Nondeterminable mean.

Femur Epiphyses

In the groups treated with gadopiclenol, gadoterate, and gadobutrol, the r1 relaxivity values were not computable (since 1/T1 − 1/T1diamagnetic values were less than 20% of the 1/T1diamagnetic value (Fig. 9C)). For 3 rats treated with gadodiamide, the 95% CI of the r1 relaxivity mean was above the in vitro reference range. For the 3 other animals, the r1 relaxivity values were not computable.

DISCUSSION

As stressed by the US Food and Drug Administration during a Medical Imaging Drugs Advisory Committee meeting in September 2017,25 preclinical models are crucial for the in-depth investigation of clinically relevant issues concerning GBCAs, which are difficult to address in patients. Sensitized animal models26 that can mimic clinical at-risk conditions are used for this purpose. The study presented here aimed at comparatively investigating the safety profile and Gd retention of the new GBCA gadopiclenol versus 2 widely used macrocyclic GBCAs and 1 linear GBCA after repeated administrations in a severe renally impaired, NSF preclinical model.

An increase in elimination half-life and a decrease in renal clearance, proportional to the degree of renal impairment, have been observed in humans for all GBCAs.27–29 In the case of gadopiclenol, it has been shown, however, that renal clearance remains complete or almost complete in patients with impaired renal function.30 In rats, renal failure also results in delayed clearance of GBCAs and, in certain cases, favors tissue retention of Gd after reiterated administrations of GBCAs, an issue especially investigated in the skin,31,32 but also observed in the brain or bone.33 In addition, almost all cases of NSF were diagnosed in patients with stage 4 or 5 CKD, or with acute kidney injury.2 Gadolinium retention and the clinical consequences associated with repeated gadopiclenol administrations were therefore compared with different categories of GBCAs in rats with severely impaired renal function. In addition to the linear GBCA gadodiamide, used as a positive control, 2 macrocyclic GBCAs were tested since they now represent the most obvious comparators for this compound. Addition of the purine derivative adenine to the diet of rats34,35 is a reproducible and minimally invasive model of postrenal failure associated with urolithiasis, which mimics several of the structural, biochemical, clinical (osteodystrophy), and functional changes seen in human CKD.36,37 The linear GBCA gadodiamide has reported36 to have the propensity to induce NSF-like effects to adenine-treated rats. The model is associated with severe renal insufficiency (approximatively 90% reduction in creatinine clearance, thus mimicking stage 5 CKD) and a dramatic decrease in body weight, hyperphosphatemia, and hyposideremia. However, these variations are reversible at the end of the adenine-enriched diet. At the end of study period, a decrease in the plasma creatinine and urea levels was noted, suggesting an improvement of renal insufficiency, although creatinine clearances remained stable.

Gadopiclenol did not induce any clinical histological or biochemical (including creatinine clearance) abnormalities suggestive of toxicity. A similar favorable profile was evidenced for the 2 marketed macrocyclic GBCAs tested, gadoterate and gadobutrol. Conversely, the nonionic and linear GBCA gadodiamide was associated with serious systemic toxicity (morbidity-mortality) and macroscopic and histological NSF-like skin lesions. Taken together, these data are fully consistent with the preclinical31,32,36 and clinical38–40 literature. In the present study, all the gadodiamide-treated animals had macroscopic skin lesions with some variations in time of occurrence (between day 4 and day 25) and severity. A detailed histological analysis was performed on skin biopsies on day 14 and day 25, to examine the NSF-like skin lesions. In the gadodiamide-treated group, all the rats showed skin lesions at both time points. The first time point was characterized by a predominance of epidermal ulcerations as well as adjacent dermal necrosis. The second time point was associated with severe acanthosis and fibroblastic densification. These lesions are compatible with the healing of the ulcerations observed at earlier time points. Dermal fibrosis appeared lately and secondary to ulceration. On day 25, a few microscopic lesions (slight increase in fibroblastic density and fibroblast activation) were observed in the dermis of 3 groups receiving macrocyclic GBCAs, but the effect was similar to that observed in the control group and was therefore regarded as not test-item related and not clinically relevant. Unlike with gadodiamide, no NSF-like dermal lesions were observed in the groups treated with the 3 macrocyclic GBCAs.

The presence of elemental (ie, without prejudice of the chemical species of the metal) Gd in various tissues was investigated during the study and/or at study completion. The Gd concentrations in the tested tissues were generally higher with gadodiamide than with the macrocyclic GBCAs, including gadopiclenol. That was the case in the skin at both time points, as well as in the femur and spleen, where gadodiamide gave rise to higher Gd concentrations than gadopiclenol and the macrocyclic agents, with which concentration ranges were similar. This is consistent with the literature31,36,41 and the hypothesis that less stable GBCAs are prone to release and lead to more Gd accumulation in tissues. It has been proposed that Gd versus endogenous metal transmetallation associated with the gradual release of profibrotic soluble Gd species in tissues may explain the mechanism of NSF.42 This effect is related to the molecular structure of the GBCA ligand, which determines its thermodynamic and kinetic stabilities.7 Gadopiclenol has a macrocyclic structure and is associated with a high kinetic stability.17 Its absence of a profibrosing effect, such as the other macrocyclic agents, may therefore be attributable to its kinetic stability. The good clinical and biochemical safety profile of gadopiclenol in our preclinical study is consistent with the safety data obtained in humans during clinical trials,18,20 including patients with mild to severe renal impairment.30 Interestingly, in the gadodiamide group, the 3 animals with higher skin Gd concentrations on day 14 showed severe skin lesions, thus suggesting a relationship between the presence of Gd and skin lesions, as already reported in other preclinical studies31,36 with this molecule. In the skin, Gd concentrations were statistically similar for gadopiclenol and the macrocyclic GBCAs gadoterate and gadobutrol on day 14 and on day 25. On the last time point, the variability is higher in the gadopiclenol group, resulting to a slightly higher mean than those of the other macrocyclic GBCAs and a lower washout between day 14 and day 25.

Since the seminal work by Kanda and colleagues,3 numerous preclinical and clinical studies (mostly retrospective) have resulted in better knowledge of the distribution and biospeciation of GBCAs in the brain tissues. Brain tissue samplings were also performed in the present study. Only traces of elemental Gd (in the micromolar range) were measured in our experimental conditions, similar to that observed with other macrocyclic GBCAs. Unlike Fretellier et al43 or Rasschaert et al,44 we did not dissect the deep cerebellar nuclei and measured elemental Gd concentration in the whole cerebellum. In the brain structures, elemental Gd concentrations were significantly higher with gadodiamide than with the macrocyclic GBCAs. This is consistent with another study performed in renally impaired rats (by subtotal fifth/sixth nephrectomy) repeatedly treated with a similar cumulative dose (12 mmol/kg) of gadoterate, gadobenate, and gadodiamide, but with a different dosing scheme (20 × 0.6 mmol/kg injections over 5 weeks) and a 1-month treatment-free period.44 In healthy adult rats repeatedly treated with various GBCAs including gadopiclenol (same cumulative 12 mmol/kg dose), at 5 months postdose, the macrocyclic compound was shown to have given rise to similar Gd levels in the cerebellum as the macrocyclic agent gadobutrol, and these were 29 times lower than those observed with gadodiamide.45

No significant between-group difference was observed in elemental Gd concentrations in the urine and feces at both time points. A major decrease was noted between day 11 and day 25. However, Gd was still detectable in the urine and feces 3 weeks after the injection period, showing the progressive elimination from the organs of the remaining Gd in a severe renally impaired model.

Similarly, no difference was observed between the GBCAs in elemental Gd concentrations in the kidney and the heart. Although the kidney function was severely impaired, the kidneys still appeared to be able to process the GBCAs and other soluble forms of Gd that were eliminated in the urine, which could explain the similar Gd levels found in the kidney parenchyma. Longer follow-up is required to investigate Gd washout from this organ. Of note, after repeated administrations of the GBCA gadopentetate to healthy rats, the tissues with the highest Gd concentration (bone, kidneys, and liver) showed virtually no decrease for up to 93 weeks. Almost 2 years after the last of 15 × 0.5 mmol/kg administrations, Gd was still measured in the kidneys46 at a concentration of ~11 nmol/g.

Unlike other tissues where no statistically significant difference between macrocyclic GBCAs was observed, a higher elemental Gd concentration was found in the liver parenchyma of rats treated with gadopiclenol versus the other macrocyclic GBCAs. The Gd concentration was similar to that found with gadodiamide. This result may be related to slightly higher fecal excretion of this compound in renally impaired rats. After intravenous administration of 153Gd-gadopiclenol to healthy rats at 0.6 mmol Gd/kg, the major route of excretion of total radioactivity in both male and female animals was the urine. However, at 168 hours postdose, fecal excretion accounted for means of 4.8% and 8.7%, respectively (regulatory study, data on file). This is slightly higher than what is typically reported for nonspecific GBCAs in this species. For example, in the case of gadobutrol, 2.3% ± 1.6% of the dose were found in the feces at 24 hours postdose (ie, an earlier time point) in the same species.47 Otherwise, the structure of gadopiclenol is different than those of other macrocyclic GBCAs.17 Its tridimensional conformation, due to the pyridine cycle planarity and to the hydrogen liaison of the alcohol groups, could therefore lead to specific interactions with endogenous molecules. Longer follow-up is required for more in-depth investigation of this observation. It is worth noting that no biochemical parameter changes suggestive of liver toxicity were found for gadopiclenol. No histopathological liver parenchyma abnormalities were observed in a similar study performed in renally impaired rats and in a 4-week repeated dose toxicology study performed in healthy rats at very high dose with this compound (regulatory study, data on file).

Electron microscopy analysis associated with Gd detection in skin biopsies was used to localize Gd deposits in the skin, as previously reported in NSF patients48–53 and in renally impaired rats.32 TEM examination was performed in 2 animals (out of 8) per group, except for the animals treated with gadoterate as it has been already studied elsewhere,32 for which no Gd deposits were evidenced in the dermis. Two slices were observed per rat, and observations were fairly reproducible in the 2 animals from a same group. The pattern of Gd deposition differed according to the GBCA tested. With regard to the macrocyclic GBCAs gadobutrol and gadopiclenol, no Gd deposits were found associated with collagen fibers and fibroblasts (which were of normal ultrastructure). Conversely, in the case of gadodiamide, insoluble Gd deposits were observed among the collagen fibers in elongated and spiky structures, surrounded by a halo driving away the fibers, reminiscent of observations made by Haylor et al32 in the dermis of renally impaired rats. These results are consistent with a distinct profile for these 2 categories of GBCAs. With gadobutrol and gadopiclenol, Gd was identified in membrane-bound dark intracellular inclusions, identified as lysosomes located in macrophages. The morphology, rough texture, and location of the Gd found by TEM analysis were similar for both macrocyclic GBCAs. To our knowledge, the presence of Gd deposits in skin macrophages has not been reported so far in the case of macrocyclic GBCAs. However, this result must be analyzed in the context of very high doses administered to animals with severe renal insufficiency.

On transversal slices, the Gd deposits have a sea urchin–like morphology and were rich in phosphorus and oxygen, as observed in the cerebellar structures of gadodiamide-treated rats.54 In gadodiamide-treated rats, Gd deposits were identified in intracellular membrane-bound dark inclusions found in the fibroblasts. This observation is again consistent with the TEM data published by Rasschaert et al.54 With this GBCA, Gd could therefore partly accumulate in the same form, independently of the tissue where it is retained. As in the groups treated with the macrocyclic GBCAs, in the gadodiamide group, Gd was also found in lysosomal inclusions in macrophages, but with a more filamentous shape. The texture of Gd deposits therefore differed according to the administered GBCAs, which may suggest different processing of the insoluble Gd retained in the skin at these early time points.

The presence of phosphorus and oxygen in the inclusions observed in the gadodiamide group is consistent with the presence of GdPO4 crystals, as mentioned in the literature,48,49,51 but this hypothesis needs to be confirmed using more precise methods.

The relaxometry method (which measures T1 proton relaxation time) combined with total Gd assay is a useful tool to indirectly investigate dissociated versus chelated states of Gd in vivo after administration of GBCA,23 despite it being only a qualitative method that provides no indications as to the location of Gd in the tissues. Calculated r1 relaxivity values are characteristic of a given species23 of Gd3+. The principle of the method is that, when r1 relaxivity values measured ex vivo in a given tissue are higher than those obtained in vitro in the same tissue matrix spiked with the tested GBCA, it can be concluded that the GBCA in question dissociated and led to the formation of soluble Gd species, probably bound to macromolecules and associated with a greater r1 relaxivity than chelated Gd. Our results showed an increase in r1 values in the liver parenchyma, femoral epiphyses, and skin samples of the gadodiamide-treated rats. These results are therefore consistent with gradual in vivo dissociation of this linear GBCA with the presence of soluble and dissociated Gd3+species. Nevertheless, other Gd species also occur, especially insoluble Gd deposits, as showed using TEM. Such insoluble Gd species are not evidenced by the method, which is here driven by the soluble species. In contrast, when the r1 relaxivity value was determinable in the tissues of gadopiclenol-treated rats (ie, liver and skin), it remained stable, suggesting that Gd remains chelated by its macrocyclic ligand. The r1 relaxivity value could not be determined for the other macrocyclic GBCAs (gadobutrol and gadoterate) in any of the investigated tissues due to the low elemental Gd concentrations in these tissues. Conversely, measurements were possible for gadopiclenol. This may be explained by its high intrinsic r1 relaxivity (12.8 mM−1 s−1 at 1.5 T in a biological medium).17 Skin and liver r1 relaxivity values were similar to the relaxivity of intact gadopiclenol in a biological milieu, consistent with an absence of dissociation. Alternatively, it may be argued that these values are close to those of soluble and “free” Gd in the same tissues (r1 of approximately 15 mM−1 s−1 for Gd acetate at 1.5 T in a biological milieu23), thus making it difficult to conclude as to a possible in vivo dissociation, which is a limitation of the technique for high-relaxivity GBCAs.

Our study has limitations; these are as follows: (a) the injection-free periods observed before euthanasia were relatively short, which may have made it more challenging to discriminate between the GBCAs; (b) no biospeciation studies were performed, although it is widely acknowledged that linear GBCAs (unlike macrocyclic GBCAs) gradually dissociate in vivo55–57; (c) dosing was very high over a short period in the context of severe renal failure, which reflects an extreme clinical situation rather than clinical routine; (d) the relaxometry method is not fully conclusive with high-relaxivity GBCA; and (e) TEM examination was limited to 2 slices per samples, in 2 animals per groups, and gadoterate samples were not analyzed in the present study. Moreover, the Gd deposits are very tiny, and the visual scanning of the slices at the lowest magnitude does not allow an exhaustive detection of their presence.

In conclusion, the safety profile of gadopiclenol, a new, high-relaxivity macrocyclic GBCA, was compared with those of marketed GBCAs of most molecular categories in a renally impaired sensitized rat model. Elemental Gd concentrations were also measured in various tissues, including the brain. Serious clinical signs and pathological abnormalities of the skin were observed in the gadodiamide-treated group, whereas no such effects were observed with the other GBCAs gadobutrol, gadoterate, and gadopiclenol. It can be concluded that no evidence of systemic, biochemical, or skin toxicity was found in adult renally impaired rats repeatedly treated with the macrocyclic GBCA gadopiclenol. Although elemental Gd tissue concentrations were similar for gadopiclenol and the macrocyclic GBCAs gadoterate and gadobutrol in most tissues (including the cerebellum and brain cortex), it was higher in the liver parenchyma.

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Keywords:

gadopiclenol; gadoterate; gadodiamide; gadobutrol; nephrogenic systemic fibrosis; renal impairment; gadolinium-based contrast agents

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