Bruno Bonnemain

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.

Safety and Tolerability of Ultrasmall Superparamagnetic Iron Oxide Contrast Agent: Comprehensive Analysis of a Clinical Development Program

Background:Because of its cellular uptake pattern, ferumoxtran-10 may be potentially useful for the imaging of a variety of diseases (eg, atheroma, multiple sclerosis, stroke, renal graft rejection, glomerulonephritis and brain tumors, in addition to differentiation of metastatic and nonmetastatic lymph nodes). The aim of this article is to present a comprehensive review of the safety and tolerability of ferumoxtran-10 as reported during clinical development of the compound as an ultrasmall superparamagnetic iron oxide contrast agent for use in magnetic resonance imaging. Materials and Methods:The safety profile of ferumoxtran-10 was assessed using pooled data from 37 phase I to III clinical studies in 1777 adults (1663 received the contrast agent [1527 patients and 136 healthy volunteers], 75 received placebo, and 39 patients were enrolled but did not receive study medication). Results:At least one adverse event was reported in 23.2% of patients who received ferumoxtran-10. Adverse events were of mild-to-moderate severity in 86.3% of patients in the ferumoxtran-10 group. At least 1 event considered by the investigator to be related to study treatment was reported in 18.2% of patients in the ferumoxtran-10 group. The most commonly reported treatment-related adverse events were back pain, pruritus, headache, and urticaria. A total of 44 patients (2.6%) in the ferumoxtran-10 group reported 76 serious adverse event (SAE). Only 7 SAEs (0.42%) were considered to be treatment-related (anaphylactic shock, chest pain, dyspnea, skin rash, oxygen saturation decreased, and 2 cases of hypotension). There were 12 deaths, only one of which (anaphylactic shock) was considered to be related to ferumoxtran-10 which was administered by bolus injection of undiluted product, a mode of administration that is no longer recommended. Results in high-risk groups of patients including the elderly and those with hepatic, renal or cardiovascular disease seemed to show no cause for special clinical concern in these groups. Conclusions:Clinical experience to date therefore shows ferumoxtran-10 to be a well tolerated contrast agent.

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.

Iodinated contrast media-induced nephropathy : pathophysiology, clinical aspects and prevention

Summary— Administration of iodinated contrast media (CM) for radiographic purposes is a preoccupying cause of acute renal failure. This review of the literature deals with what is known about physiopathology, clinical course, risk factors and prevention. Factors involved in the pathophysiology of CM‐induced acute renal failure are vasoconstriction, direct tubular cell injury and tubular obstruction by casts. In the case of pre‐existing renal hypoperfusion, CM may disturb the complex interaction between factors which modulate renal haemodynamics by increasing vasoconstrictor factors, notably endothelin peptides. The renal medulla, a zone characterized by a high metabolic activity and a low oxygen tension, may be a specific target for CM‐induced effects. CM‐induced nephropathy (CMN) is essentially observed in patients with one or more associated risk factors (chronic renal failure, dehydration, diabetes mellitus with impaired renal function, multiple myeloma, large CM volume, intra‐arterial rather than intravenous route, etc). There is much debate as to whether newer low osmolar CM (LOCM) are better tolerated than conventional high osmolar CM (HOCM). Most of the animal studies clearly demonstrate the advantages of LOCM over HOCM. Clinical literature is far more confusing, although some recent studies and one meta‐analysis demonstrate that LOCM are better tolerated in patients with impaired renal function. The low number of comparative clinical trials carried out in high risk patients, wide variability in CMN definitions, limited number of patients enrolled and inadequacy of various selected endpoints may explain difficulties experienced in demonstrating this advantage. Furthermore, while hydration is correctly maintained during clinical trials, this is not always true in clinical practice. Such a discrepancy could lead to underestimation of the potential advantage of LOCM over HOCM. Effective prevention should associate the correct hydration of patients, identification and, when possible, optimal correction of risk factors, avoidance of repeated CM injections within a short period of time and temporary disruption of treatment with other nephrotoxic drugs (non steroidal antiinflammatory drugs, aminoglycosides, etc).

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.

experimental Study of Dota-gadolinium Pharmacokinetics and Pharmacologic Properties

Allard M, Doucet D, Kien P, Bonnemain B, Caillé JM. Experimental study of DOTA‐gadolinium: pharmacokinetics and pharmacologic properties. Invest Radiol 1988;23(Suppl 1):S271‐S274. Pharmacokinetic and acute‐toxicity studies of Gd‐DOTA meglumine (Mgl) were evaluated in various animals and compared with those of Gd‐DTPA Mgl. The agents were injected intravenously at two dosages: 0.1 or 0.5 mmol/kg. Various organs and tissues were removed at specified times after injection and assayed for gadolinium (Gd) concentration. The two complexes behave in an identical fashion in their short‐term biodistribution and excretion. The very rapid distribution in the body (except in the brain) and the high clearance from blood are due to an extravascular distribution. The small distribution volume and the very high hydrophilicity account for its extracellular localization. There is no accumulation within any organ. Rapid disappearance, short half‐life, size, and hydrophilicity of these molecules are in agreement with urinary elimination by free glomerular filtration. Whatever the species or the salt used, Gd‐DOTA appears safer in its acute toxicity than Gd‐DTPA with an 85% higher safety factor. These results can be explained by the greater stability of Gd‐DOTA (very slow kinetics of dissociation and greater specificity of DOTA than DTPA for gadolinium), and the lower osmolality of DOTA than DTPA. The pharmacokinetic characteristics and the very low toxicity of Gd‐DOTA Mgl may prove its suitability for intravenous or oral administration in humans.

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.

Gd-DOTA, a potential MRI contrast agent. Current status of physicochemical knowledge.

Meyer D, Schaefer M, Bonnemain B. Gd‐DOTA, a potential MRI contrast agent: current status of physicochemical knowledge. Invest Radiol 1988;23(Suppl 1):S232‐S235. The complex (Gd‐DOTA) meglumine has recently been used as an MRI contrast agent in humans. Due to its particularly interesting physicochemical properties, the risk of in vivo dissociation of the complex is reduced. Indeed, as a result of the macrocyclic nature of the DOTA ligand, Gd‐DOTA appears very stable, demonstrating a calculated conditional stability constant of 1022.19 at pH = 7. Other characteristics making Gd‐DOTA a positively attractive compound include slow dissociation kinetics inherent in the rigidity of the macrocycle and marked specific affinity of DOTA for gadolinium in comparison with other endogenous ions. Finally, although the relaxivity R1 of Gd‐DOTA at 20 MHz appears similar to that of Gd‐DTPA, Gd‐DOTA demonstrates higher paramagnetic efficacy at low field strength due to greater symmetry of the complex. Such promising properties open up wide prospects for the use of Gd‐DOTA in MRI.

Haemodynamic effects of macrocyclic and linear gadolinium chelates in rats: role of calcium and transmetallation

Several studies were undertaken to compare four magnetic resonance imaging (MRI) contrast media (CM) as regards acute haemodynamic effects in rats and to investigate the mechanisms involved. (1) Normotensive rats received a rapid bolus intravenous injection of 0.5 mmol kg of each CM. The effects of Gd-DOTA, Gd-HP-DO3A, Gd-DTPA and Gd-DTPA-BMA on blood pressure (BP) were compared. (2) The haemo-dynamic effects of Gd-DTPA (0.5 mmol kg ) were compared to those of isovolumic and isoosmolar Zn-DTPA and glucose solutions. (3) The haemodynamic profiles of Gd-DTPA and Gd-DTPA-BMA were recorded with and without addition of ionized calcium. (4) The mechanism of Gd-HP-DO3A-induced tran-sient rise in BP was investigated by evaluating the effects of phentolamine or diltiazem pretreatment. For (1) the greatest drop in BP occurred following Gd-DTPA (a linear chelate) injection (–18 ± 2% vs base-line, P < 0.01). Gd-DTPA-BMA, another lineate chelate, also induced a slight but significant reduction in BP (–8 ± 2% at 45 s, P < 0.05). Gd-DOTA, a macrocyclic CM, had virtually no haemodynamic effects. For (2) the Gd-DTPA-induced drop in BP was greater than that of the osmolality-matched glucose control and lower than that of osmolality-matched Zn-DTPA. For (3) a transmetallation phenomenon versus free ionized calcium is possible in the case of both linear CM (Gd-DTPA and Gd-DTPA-BMA) since Ca significantly reduced the CM-induced decrease in BP. For (4) a transient rise in BP was observed following Gd-HP-DO3A, another macrocyclic chelate, associated with a concomitant increase in stroke volume. This effect was antagonized neither by phentolamine nor by diltiazem. The decrease in BP following injection of Gd-DTPA or Gd-DTPA-BMA may not only be osmolality-related since (a) Gd-DOTA solution, whose osmo-lality is greater than that of Gd-DTPA-BMA, had a lesser effect, and (b) this hypotensive effect was corrected by addition of ionized calcium. The transient Gd-HP-DO3A-induced rise in BP is probably the consequence of a positive inotropic effect.

Iobitridol, a new nonionic low-osmolality contrast agent, and iohexol. Impact on renal histology in the rat.

RATIONALE AND OBJECTIVESTo compare the histologic effects on rat tubular cells of two nonionic contrast media with equivalent osmolalities and viscosities. METHODSHistologic, functional (creatinine clearance), and biochemical (proteinuria and enzymuria) profiles of iohexol and iobitridol (both at 350 mg 1/mL) were compared in the uninephrectomized rat. A control group (n = 14) received compared isotonic saline solution. Test substances (3 mL) were injected into the kidney at a rate of 1 mL/minute while transitory ischemia was induced by clamping the aorta above the renal artery. RESULTSIn terms of their (moderate) effects on creatinine clearance, proteinuria, and urinary N-acetyl-beta–D-glucosaminidase activity, no statistically significant difference was detected between the two low-osmolar contrast agents either 24 or 48 hours after injection. However, blinded histologic analysis of the kidneys showed significantly greater epithelial cell vacuolization in the proximal convoluted tubules of the outer cortex with iohexol (14 of 14 rats versus 3 of 14 rats for iobitridol; P < .001). The same degree of vacuolization in the inner cortex was observed for all three substances. Iobitridol also induced fewer congestive lesions in the glomerular capillaries than iohexol (4 of 14 versus 10 of 14, respectively; P < .05) and saline (5 of 6; P < .05). It is difficult to explain the lesser degree of cytoplasmic vacuolization using standard physiochemical parameters. CONCLUSIONAlthough iobitridol and iohexol showed similar functional and biochemical profiles when selectively injected into the single remaining kidney of rats, iobitridol induced significantly less tubular vacuolization and capillary congestion than iohexol.