A Review of Preclinical Safety Data for Magnevist (Gadopentetate Dimeglumine) in the Context of Nephrogenic Systemic Fibrosis

Abstract

Magnevist (gadopentetate dimeglumine, Bayer Healthcare, Bayer) is a gadolinium-based contrast agent (GBCA) for magnetic resonance imaging approved for clinical use in various indications since 1988. A possible association between the administration of GBCAs to patients with severe kidney impairment, and a condition first identified in 2000 and later described as "nephrogenic systemic fibrosis" (NSF), was published in early 2006. In the light of this reported association and the published histologic findings of certain NSF patients, Bayer, with support of external experts, reassessed the preclinical safety data from in vivo studies in healthy rats and dogs that were conducted with Magnevist during the drug development process in the mid-80s. These studies, which were performed according to standard regulatory requirements as defined in pertinent guidelines and which were conducted before the reported association between GBCAs and NSF, were not specifically designed to detect NSF-like lesions. Instead, the intention of this reassessment was to analyze whether the acquired knowledge on NSF would lead to a revised interpretation of the original preclinical data. Studies on repeat-dose toxicity of Magnevist performed in the mid-80s with healthy rats and dogs were re-evaluated, with special emphasis on the retrospective analysis of morphologic findings which have come to be considered potentially suggestive of NSF. In particular, histologic slides of the skin of repeat-dose toxicity studies were re-examined by Bayer pathologists, with a special focus on the occurrence of morphologic lesions that have subsequently been identified as consistent with NSF. In addition, slides from selected studies were also subjected to a blinded external peer review by an independent international Pathology Working Group. A review of the preclinical data from the repeated-dose toxicity studies provided no evidence for toxicological effects after administration of Magnevist, which could be construed as suggestive of or consistent with NSF. More specifically, histopathology peer reviews of skin samples from repeated-dose toxicity studies with rats and dogs revealed no signs of skin lesions even after repeated high-dose administration to rats of 5.0 mmol Gd/kg of Magnevist (50 times the standard diagnostic dose). No findings were observed in any of the preclinical studies with Magnevist in healthy rats and dogs which could be characterized as similar to the types of morphologic lesions that have subsequently been identified as consistent with NSF. This preclinical assessment is in contrast to the reported clinical evidence of rare NSF cases in patients with severe kidney impairment after Magnevist administration. The differences between the preclinical models and their predictive limitations with regard to the clinical situation of renally impaired patients are discussed.