Work

In Vitro Stability and Preclinical Safety Evaluation of High-Dose Intravitreal Topotecan in Rabbits: Impact of Dose and Concentration

Year: 2025

Type: article

Abstract: Purpose To assess the stability of concentrated solutions of topotecan and the ocular and systemic safety of administering repeated very high doses of intravitreal topotecan in rabbits. Design Experimental study. Subjects Twenty four non-tumor-bearing New Zealand White rabbits. Main Outcome Measures In vitro stability of topotecan solutions, hematologic parameters, fundoscopic examination, electroretinography response, fundoscopic photography, and histologic assessment. Methods Three topotecan solutions (1-4mg/ml) were assessed for stability at 4°C and -20°C for 1 month of drug reconstitution. Five groups of non-tumor-bearing rabbits were used to evaluate systemic and ocular toxicity of three monthly doses of topotecan (50μg, 100μg, and 200μg) injected in 50μL or in 100μL of diluent, or receiving only the vehicle. Ophthalmic, clinical, and electroretinographic evaluations were performed monthly. One month after the last injection, all eyes were enucleated for histological assessment. Electroretinographic parameters were compared among groups using a linear mixed-effects model (p<0.05). Results Topotecan solutions remained stable. During the study period, no hair loss, weight changes, or hematologic abnormalities were observed in any of the animal groups. Eyes treated with vehicle or injected with three doses of topotecan up to 100μg per dose, delivered in either 50μL or 100μL diluent, showed no morphological, histological, or functional evidence of damage to the retina. However, eyes injected with 200μg showed localized retinal alterations near the injection site on fundoscopy and histological analysis, and a significant decrease in the a - and b -wave amplitudes on electroretinography compared to the other groups ( p < 0.05). Conclusions Three monthly intravitreal injections of topotecan 50 or 100μg (100μg and 200μg human equivalent doses), caused no systemic or ocular toxicity in a non-tumor-bearing rabbit model. Repeated 200μg doses (400μg human equivalent dose) resulted in localized retinal morphological alterations and small but detectable changes in electrophysiological parameters. The results of this study may have clinical utility in the assessment of very high-dose topotecan as a salvage treatment of highly compromised eyes with recurrent or relapsed subretinal seeds and retinal tumors.

Source: Ophthalmology Science

DOI: 10.1016/j.xops.2025.100963