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Ocular toxicity of AUY922 in pigmented and albino rats
Danielle Roman1, James VerHoeve2, Heiko Schadt1
1Preclinical Safety, Novartis Pharma AG, Basel, Switzerland.
Abstract:
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 30mg/kg of AUY922, the AUC0-24h and Cmax are comparable to that in patients at 70mg/m(2). AUY922 at ≥30mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment. Electroretinography (ERG) changes were observed at doses ≥30mg/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 Cmax while maintaining AUC. Histopathological changes were seen mainly when rats were administered AUY922 at 100mg/kg. The 2-hour infusion of AUY922 at 100mg/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 100mg/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.
Insights
AUY922, a heat shock protein 90 inhibitor, caused reversible retinal toxicity in rats, affecting photoreceptors. These findings in rats mirror patient outcomes, though the exact molecular cause remains unknown.
Area of Science:
- Pharmacology
- Toxicology
- Ophthalmology
Background:
- AUY922 is a heat shock protein 90 inhibitor.
- Ocular adverse events (AEs) have been associated with AUY922 treatment.
- Understanding these ocular AEs is crucial for patient safety.
Purpose of the Study:
- To investigate the ocular adverse events of AUY922 in a preclinical rat model.
- To assess the impact of AUY922 on retinal structure and function.
- To characterize the reversibility and dose-dependency of AUY922-induced ocular toxicity.
Main Methods:
- Four investigative studies were conducted in pigmented (Brown Norway) and albino (Wistar) rats.
- Dose-ranging studies with AUY922 administration (≥30mg/kg).
- Electroretinography (ERG) and histopathology were used to assess retinal function and structure.
Main Results:
- AUY922 at ≥30mg/kg led to dose-dependent, reversible ERG changes indicative of photoreceptor effects.
- Histopathological changes, including outer segment disorganization, were observed at 100mg/kg but were reversible.
- No significant differences in ocular response were noted between rat strains.
- No changes in key retinal proteins (rhodopsin, PDE6, transducin, RPE65) or serum iron were detected.
Conclusions:
- AUY922 causes reversible retinal toxicity in rats, consistent with observations in patients.
- The observed effects are dose-dependent and primarily impact photoreceptor structure and function.
- While toxicity is reversible, the precise molecular mechanism underlying AUY922's ocular effects requires further investigation.
