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Topotecan Vitreous Levels after Periocular or Intravenous Delivery in Rabbits: An Alternative for Retinoblastoma Chemotherapy

¹From the Departments of Pharmacology, ⁴Pharmaceutical Technology, and ⁶ININFA (CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina; the ²Departments of Hemato-oncology, ³Ophthalmology, and ⁵Pathology, Hospital J.P. Garrahan, Buenos Aires, Argentina; and the ⁷Department of Ophthalmic Oncology, Radiotherapy and Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.

PURPOSE. To determine the extent and the mechanism by which topotecan, a candidate agent for the treatment of retinoblastoma, gains access to the vitreous when administered by periocular injection or intravenous infusion.

METHODS. In vivo experiments were conducted in which albino rabbits received 1 mg topotecan by periocular injection (POI group; n = 30) or as a 30-minute intravenous infusion (IV group; n = 16). Plasma and vitreal topotecan concentrations were analyzed during the 10 hours after administration. A population pharmacokinetic model was fit to the data. Additionally, periocular injections were performed postmortem to study the effect of removing the blood vasculature barrier.

RESULTS. Potentially active lactone topotecan levels were detected in the vitreous in the POI and IV groups. Both administration schedules induced high total topotecan plasma exposures because of absorption from the periocular depot, though plasma lactone area under the curve (AUC) was significantly higher in the IV group. Similar vitreal concentrations were found in treated and control eyes in the POI group. The transfer from the periocular compartment to the vitreous was negligible. The absence of drug levels in the control eye of the postmortem-injected rabbits confirmed the systemic delivery of topotecan. Local toxicity was not observed.

CONCLUSIONS. As a consequence of a favored passage across the blood–retinal barrier, considerable topotecan vitreous levels were detected in a rabbit model after systemic or periocular administration. Transscleral entry in vivo was constrained by rapid clearance from the administration site.

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