Ocular toxicity of AUY922 in pigmented and albino rats
- Preclinical Safety, Novartis Pharma AG, Basel (Switzerland)
- Ocular Services on Demand, Madison, WI (United States)
- Preclinical Safety, Novartis Pharmaceuticals Corporation, East Hanover, NJ (United States)
- Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH (United States)
- Covance Laboratories Inc., Madison, WI (United States)
- Comparative Ophthalmic Research Laboratory (CORL), University of Wisconsin, Veterinary Medical Teaching Hospital, Madison, WI (United States)
- Drug Metabolism and Pharmacokinetics, Novartis Pharmaceuticals Corporation, East Hanover, NJ (United States)
- Biologics Clinical Pharmacology, Janssen BioTherapeutics at Johnson & Johnson, Spring House, PA (United States)
- Oncology Global Development, Novartis Pharma AG, Basel (Switzerland)
AUY922, a heat shock protein 90 inhibitor is associated with ocular adverse events (AEs). To provide a better understanding of ocular AEs in patients, 4 investigative studies were performed in a step-wise approach to assess retinal structure and function in pigmented (Brown Norway) and albino (Wistar) rats. In rats administered 30 mg/kg of AUY922, the AUC{sub 0–24} {sub h} and C{sub max} are comparable to that in patients at 70 mg/m{sup 2}. AUY922 at ≥ 30 mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment. Electroretinography (ERG) changes were observed at doses ≥ 30 mg/kg. The ERG changes were dose dependent, consistent with an effect on the photoreceptors, and fully reversible. The ERG effects could not be minimized by decreasing the C{sub max} while maintaining AUC. Histopathological changes were seen mainly when rats were administered AUY922 at 100 mg/kg. The 2-hour infusion of AUY922 at 100 mg/kg caused disorganization of the outer segment photoreceptor morphology in male Brown Norway rats; the severity of the disorganization increased with the number of administrations, but was reversible during a 4-week posttreatment period. There was no major difference in ocular response between Brown Norway and Wistar rats. No changes in serum iron levels, and no changes in rhodopsin, PDE6α, β-transducin concentrations, or retinal pigment epithelium-specific protein RPE65 expression were observed after single and multiple infusions of AUY922 at 100 mg/kg compared to vehicle-treated controls. AUY922 retinal toxicity in rats recapitulates and further characterizes that reported in patients and is shown to be reversible, while a precise molecular mechanism for the effect was not determined. - Highlights: • Ocular toxicity of AUY922 was assessed in Brown Norway and Wistar rats. • AUY922 at ≥ 30 mg/kg was generally not well tolerated by rats. • Electroretinography (ERG) changes were observed at doses ≥ 30 mg/kg. • ERG changes at doses ≥ 30 mg/kg were dose-dependent, and fully reversible.
- OSTI ID:
- 22690813
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Vol. 309; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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