Anne Dencausse

Preclinical Safety and Pharmacokinetic Profile of Ferumoxtran-10, an Ultrasmall Superparamagnetic Iron Oxide Magnetic Resonance Contrast Agent

Objectives:This report presents an overview of preclinical data available on ferumoxtran-10, an ultrasmall superparamagnetic iron oxide nanoparticular contrast agent proposed for lymph node magnetic resonance imaging. Materials and Methods:Pharmacokinetic, safety pharmacology, single- and repeat-dose toxicity, reproduction toxicity, and genotoxicity studies were performed with ferumoxtran-10 given intravenously (bolus injection) in mice, rats, rabbits, dogs, and monkeys. Results:Ferumoxtran-10 was taken up by macrophages, mostly in liver, spleen, and lymph nodes, within 24 hours after bolus injection and underwent progressive metabolism. Toxicity was observed only at very high exposure levels and mainly was linked to a massive iron load after repeated injections. Ferumoxtran-10 was not mutagenic but was teratogenic in rats and rabbits. Discussion:The preclinical pharmacokinetic and safety profile of ferumoxtran-10 appears to be satisfactory in view of its proposed use as a single-dose diagnostic agent in human for MR imaging of lymph nodes.

P792: a rapid clearance blood pool agent for magnetic resonance imaging: preliminary results

An original MRI contrast agent, called P792, is described. P792 is a gadolinium macrocyclic compound based on a Gd-DOTA structure substituted by hydrophilic arms. The chemical structure of P792 has been optimized in order to provide (1) a high r1 relaxivity in the clinical field for MRI: 29 mM−1 x s−1 at 60 MHz. (2) a high biocompatibility profile and (3) a high molecular volume: the apparent hydrodynamic volume of P792 is 125 times greater than that of Gd-DOTA. As a result of this high molecular volume, P792 presents an unusual pharmacokinetic profile, as it is a Rapid Clearance Blood Pool Agent (RCBPA) characterized by limited diffusion across the normal endothelium. The original pharmacokinetic properties of this RCBPA are expected to be well suited to MR coronary angiography, angiography, perfusion imaging (stress and rest), and permeability imaging (detection of ischemia and tumor grading). Further experimental imaging studies are ongoing to define the clinical value of this compound.

Physicochemical and biological evaluation of P792, a rapid-clearance blood-pool agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES To summarize the physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P792, a new monogadolinated MRI blood-pool agent. METHODS The molecular modeling of P792 was described. The r1 relaxivity properties of P792 were measured in water and 4% human serum albumin at different magnetic fields (20, 40, 60 MHz). The stability of the gadolinium complex was assessed. The pharmacokinetic and biodistribution profiles were studied in rabbits. Renal tolerance in dehydrated rats undergoing selective intrarenal injection was evaluated. Hemodynamic safety in rats and in vitro histamine and leukotriene B4 release were also tested. RESULTS The mean diameter of P792 is 50.5 A and the r1 relaxivity of this monogadolinium contrast agent is 29 L x mmol(-1) x s(-1) at 60 MHz. The stability of the gadolinium complex in transmetallation is excellent. The pharmacokinetic and biodistribution profiles are consistent with that of a rapid-clearance blood-pool agent: P792 is mainly excreted by glomerular filtration, and its diffusion across normal endothelium is limited. Renal and hemodynamic safety is comparable to that of the nonspecific agent gadolinium-tetraazacyclododecane tetraacetic acid. No histamine or leukotriene B4 release was found in RBL-2H3 isolated mastocytes. CONCLUSIONS The relaxivity of P792 at clinical field is very high for a monogadolinium complex without protein binding. The pharmacokinetic and biodistribution profiles are consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Experimental and clinical studies are underway to confirm the potential of P792 in MRI.

Involvement of gadolinium chelates in the mechanism of nephrogenic systemic fibrosis: an update.

Nephrogenic systemic fibrosis (NSF) is a highly debilitating scleroderma-like disease occurring exclusively in patients with severe or end-stage renal failure. Since the recognition of a link between gadolinium chelates (GCs) used as contrast agents for MR imaging and NSF by two independent European teams in 2006, numerous studies have described the clinical issues and investigated the mechanism of this disease. So far the most commonly reported hypothesis is based on the in vivo dechelation of GCs. The physicochemical properties of GCs, especially their thermodynamic and kinetic stabilities, are described in the present article. High kinetic stability provided by the macrocyclic structure, combined with high thermodynamic stability, minimizes the amount of free gadolinium released in the body. The current hypotheses regarding the pathophysiologic mechanism are critically discussed.

Development of a Magnetic Resonance Imaging Protocol for the Characterization of Atherosclerotic Plaque by Using Vascular Cell Adhesion Molecule-1 and Apoptosis-Targeted Ultrasmall Superparamagnetic Iron Oxide Derivatives

Objective—Acute ischemic events are often caused by the disruption of lipid-rich plaques, which are frequently not angiographically visible. Vascular cell adhesion molecule-1 and apoptotic cell-targeted peptides studied during our previous work were conjugated to ultrasmall superparamagnetic iron oxide (USPIO) (USPIO-R832 for vascular cell adhesion molecule-1 targeting; USPIO-R826 for apoptosis targeting) and assessed by magnetic resonance imaging. Methods and Results—Apolipoprotein E knockout mice were injected with 0.1 mmol Fe/kg body weight and were imaged on a 4.7-T Bruker magnetic resonance imaging until 24 hours after contrast agent administration. Aortic samples were then harvested and examined by histochemistry, and the magnetic resonance images and histological micrographs were analyzed with ImageJ software. The plaques enhanced by USPIO-R832 contained macrophages concentrated in the cap and a large necrotic core, whereas USPIO-R826 produced a negative enhancement of plaques rich in macrophages and neutral fats concentrated inside the plaque. Both USPIO derivatives colocalized with their target on histological sections and were able to detect plaques with a vulnerable morphology, but each one is detecting a specific environment. Conclusion—Our vascular cell adhesion molecule-1 and apoptotic cell targeted USPIO derivatives seem to be highly promising tools for atherosclerosis imaging contributing to the detection of vulnerable plaques. They are able to attain their target in low doses and as fast as 30 minutes after administration.

Comparative in vivo dissociation of gadolinium chelates in renally impaired rats: a relaxometry study.

Purpose:Investigation of dissociated versus chelated gadolinium (Gd) in plasma, skin, and bone of rats with impaired renal function after administration of ionic macrocyclic (gadoterate or Dotarem) or nonionic linear (gadodiamide or Omniscan) Gd chelates. Materials and Methods:Subtotally nephrectomized Wistar rats were subjected to receive daily injections of 2.5 mmol/kg of Omniscan, gadodiamide without excess ligand caldiamide, Dotarem, or saline (n = 7–10 rats/group) for 5 consecutive days. The Gd concentration was measured by inductively coupled plasma mass spectrometer in skin, femur epiphysis, and plasma on completion of the study (day 11), and dissociated Gd3+ was measured in the plasma at day 11 (liquid chromatography inductively coupled plasma mass spectrometry). The r1 relaxivity constant was measured in skin (at day 4 and day 11) and bone (day 11) to investigate the dissociated or chelated form of Gd found in tissue samples. Clinical and skin histopathologic studies were performed. Results:Subtotal nephrectomy decreased creatinine clearance by 60%. No macroscopic skin lesions were observed in the Dotarem and Omniscan groups in contrast with the gadodiamide group (2 rats survived the study period and 4 of 10 rats showed skin ulcerations and scabs). Skin histopathologic lesions were in the range gadodiamide > Omniscan > Dotarem (similar to control rats). At day 11, the skin Gd concentration was lower in the Dotarem group (161.0 ± 85.5 nmol/g) as compared with the Omniscan (490.5 ± 223.2 nmol/g) and gadodiamide groups (mean value, 776.1 nmol/g; n = 2 survivors). The total Gd concentration in the femur was significantly higher in the Omniscan group than in the Dotarem group. At day 11, the dissociated Gd3+ concentration in plasma was below the limit of detection in the Dotarem group and was 1.5 ± 0.7 &mgr;mol/L in the Omniscan group corresponding to 62% ± 15% of the total Gd concentration. The dissociated Gd3+ concentration was 1.1 &mgr;mol/L in gadodiamide rats (n = 2 survivors). In the skin, the in vivo r1 relaxivity value increased from 4.8 ± 0.7 mM−1s−1 at day 4 to 10.5 ± 3.9 mM−1s−1 at day 11 in the Omniscan group, P < 0.05 (in vitro r1 in skin, 3.5 mM−1s−1) and gadodiamide group, whereas no significant change was observed in the Dotarem group (2.8 ± 0.2 and 4.9 ± 2.8 mM−1s−1 at day 4 and 11, respectively, NS) (in vitro value in the skin, 3.2 mM−1s−1). In the femur, the in vivo r1 relaxivity was higher in the Omniscan group (8.9 ± 2.1 mM−1s−1) (in vitro relaxivity, 4.5 mM−1s−1) and gadodiamide group (8.8 mM−1s−1, n = 2 survivors) than in the Dotarem group (3.8 mM−1s−1, n = 1 rat with measurable r1, since for 7 rats, 1/T1 − 1/T1(diamagnetic) <10% of 1/T1(diamagnetic) because of low Gd concentration) (in vitro relaxivity value in the femur matrix, 3.1 mM−1s−1). Conclusions:Unlike Dotarem, Omniscan and gadodiamide induced histologic skin lesions. At day 11, a higher Gd concentration was found in both skin and femur of Omniscan- and gadodiamide-treated rats than in Dotarem-treated rats. Relaxometry results indicate gradual in vivo dechelation and release of dissociated Gd3+ in a soluble form in renally impaired rats receiving Omniscan and gadodiamide, whereas Dotarem remained stable over the study period.

Physical, chemical, and biological evaluations of P760: a new gadolinium complex characterized by a low rate of interstitial diffusion.

An original gadolinium chelate, termed P760, which diffuses through the vascular endothelium but at a much lower rate than nonspecific agents (NSA), is described. P760 is a gadolinium macrocyclic compound based on a DOTA structure that is substituted by hydrophilic bulky groups branched on the amino‐carboxylic residues.The molecular weight is 5293, and the molecular volume, measured by light scattering, is 30 times higher (11.5 nm3) than that of gadolinium (Gd)‐DOTA (0.38 nm3). The increase in molecular volume and weight has two consequences: a) higher relaxivity (r1; 24.7 mM−1 • s−1 compared with 3.4 mM−1 • s−1 for Gd‐DOTA at 20 Mhz, 37°C); and b) a lengthening of its transport rate through the endothelium. P760 presents a peculiar pharmacokinetic profile: at early times post injection, the blood concentrations are higher than those of Gd‐DOTA, but after 20 minutes, the blood concentrations are equal for the two compounds. The body clearances of the products are identical (ie, glomerular filtration rate). P760 molecules are large enough to have a restricted diffusion through the endothelium but, conversely, small enough to pass freely through the glomerular membrane. This limited extravasation has been observed in rabbits by magnetic resonance angiography or in investigations of tumor permeability. Further experimental imaging studies are needed to define the clinical interest of such properties. J. Magn. Reson. Imaging 2000;11:182–191.

P760 and P775: MRI contrast agents characterized by new pharmacokinetic properties.

Rationale and objectives: In this paper we discuss novel MR imaging blood pool agents characterized by new pharmacokinetic properties.Methods: The pharmacokinetics of the products were studied in a rabbit model. The potential of these new products was demonstrated in experimental MR imaging.Results and conclusion: Three main classes of blood pool agents have been defined and characterized according to their pharmacokinetic properties: low diffusion agents, rapid clearance blood pool agents, slow clearance blood pool agents. Each kind of blood pool agent is expected to have different diagnostic applications.

Nephrogenic gadolinium biodistribution and skin cellularity following a single injection of Omniscan in the rat.

Objectives:The development of nephrogenic systemic fibrosis (NSF) following MRI contrast examination has been associated with gadolinium (Gd) toxicity. Animal models should show the key features of NSF in man where, the only immutable epidemiological feature is renal impairment. A rat model of chronic renal insufficiency has been employed to establish whether tissue gadolinium retention and increased skin cellularity following a gadolinium based contrast agent (GBCA) can be correlated with a reduction in renal function. The GBCA chosen for investigation was Omniscan, the least stable of the commercially available agents. Materials and Methods:Wistar rats were subjected to 5/6 subtotal nephrectomy (SNx) under isoflurane anesthesia. The glomerular filtration rate (GFR) was assessed from serum creatinine and creatinine clearance. Two SNx rats groups were established, following either 75% or 80% resection of the kidney, which reduced the GFR down to 40% and down to 20%, respectively, of sham-operated controls. Three months after surgery, rats received a single intravenous injection of either saline or Omniscan (gadodiamide 2.5 mmol/kg). Four weeks later, the Gd content of serum, skin, liver, and bone was measured by inductively coupled plasma mass spectrometry and skin cellularity determined. Results:In sham-operated rats, Gd was detected in skin < liver < bone. SNx rats with the GFR reduced down to 20% normal, had an increased tissue Gd concentration in bone (2.5-fold), skin (3-fold), and liver (10-fold) compared with sham-operated controls. The Gd concentration in all 3 tissues showed a positive linear correlation with serum creatinine (P < 0.01). No external skin lesions were observed. The skin cellularity of rats with the GFR reduced down to 20% of normal was increased following Omniscan, together with positive immunostain for CD34 and prolyl-4-hydroxylase. Conclusions:The SNx rat is a sensitive model for investigating the pathophysiology of NSF. A positive linear correlation was obtained between tissue Gd and serum creatinine, the major clinical marker of renal function. An increase in skin cellularity, a feature of human NSF, was demonstrated in rats with a level of renal impairment equivalent of stage 4 chronic kidney disease following just a single intravenous dose of Omniscan. This response was obtained in the absence of ulcerogenic skin lesions, at skin Gd concentrations as low as 50 nmol/g.

Comparison of plasma and peritoneal concentrations of various categories of MRI blood pool agents in a murine experimental pharmacokinetic model

The aim of this study was to validate an experimental model designed to distinguish four categories of contrast agents, non specific agents (NDA, Gd-DOTA) characterized by rapid and total extravasation; low diffusion agents (LDA, P760) characterized by delayed extravasation; and rapid (P792) and slow clearance (P717) blood pool agents (BPA) characterized by limited extravasation.Plasma and peritoneal gadolinium concentrations were simultaneously measured after intravenous injection of various contrast agents in mice. Products of each category were compared in this model.The plasma pharmacokinetic profiles were similar for Gd-DOTA and P760 (t1/2 = 13.3 and 13.8 min. respectively), whereas the half-lives were 22 and 1212 min for P792 and P717, respectively. The plasma clearance was inversely related to the size of the contrast agent. The intraperitoneal diffusion patterns of the various products were related to the molecular volume; Cmax per dose decreased progressively (78.7, 51.2, 44.2, 33.5 1/1) and tmax increased (7, 15, 40, and 120 min) for Gd-DOTA, P760, P792 and P717, respectively. Nevertheless, the same quantities of Gd-DOTA and P760 (AUC ratio of 78.4 and 76.8, respectively) diffused into the peritoneum, whereas only 44.5% of P792 and 21.5% of P717 extravasated.The data obtained in this peritoneal permeability model with the various categories of contrast agents provide an estimation of the quantities of contrast agents diffusing into a permeable interstitium and may be used to predict the corresponding signal intensity, which can be measured locally.