title: Ocular toxicity of AUY922 in pigmented and albino rats.
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.
authors: Preclinical Safety, Novartis Pharma AG, Basel, Switzerland. Electronic address: danielle.roman@novartis.com.
authors: Danielle
authors: D
authors: Roman
authors: Ocular Services on Demand, Madison, WI, USA; University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors: James
authors: J
authors: VerHoeve
authors: Preclinical Safety, Novartis Pharma AG, Basel, Switzerland.
authors: Heiko
authors: H
authors: Schadt
authors: Preclinical Safety, Novartis Pharma AG, Basel, Switzerland.
authors: Axel
authors: A
authors: Vicart
authors: Preclinical Safety, Novartis Pharma AG, Basel, Switzerland.
authors: Ursula Junker
authors: UJ
authors: Walker
authors: Preclinical Safety, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors: Oliver
authors: O
authors: Turner
authors: Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, USA.
authors: Terrilyn A
authors: TA
authors: Richardson
authors: Covance Laboratories Inc., Madison, WI, USA.
authors: Suzanne T
authors: ST
authors: Wolford
authors: Comparative Ophthalmic Research Laboratory (CORL), University of Wisconsin, Veterinary Medical Teaching Hospital, Madison, WI, USA.
authors: Paul E
authors: PE
authors: Miller
authors: Drug Metabolism and Pharmacokinetics, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors: Wei
authors: W
authors: Zhou
authors: Biologics Clinical Pharmacology, Janssen BioTherapeutics at Johnson & Johnson, Spring House, PA, USA.
authors: Hong
authors: H
authors: Lu
authors: Oncology Global Development, Novartis Pharma AG, Basel, Switzerland.
authors: Mikhail
authors: M
authors: Akimov
authors: Preclinical Safety, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors: William
authors: W
authors: Kluwe
mesh_terms: D000818:Animals; D004596:Electroretinography; D005123:Eye / Q000187:drug effects* / Q000503:physiopathology; D007555:Isoxazoles / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012118:Resorcinols / Q000633:toxicity
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D007555:Isoxazoles; D012118:Resorcinols
keywords: AUY922; Electroretinography; HSP90 inhibitor; Histopathology; Ocular toxicity; Rodents