Pharmacokinetic analysis of topotecan after intra-vitreal injection. Implications for retinoblastoma treatment.

Abstract

Topotecan is a promising drug with activity against retinoblastoma, however, attaining therapeutic concentrations in the vitreous humor is still a challenge for the treatment of vitreous seeds in retinoblastoma. Our aim was to characterize topotecan pharmacokinetics in vitreous and aqueous humor, and to assess the systemic exposure after intra-vitreal injection in rabbits as an alternative route for maximizing local drug exposure. Anesthetized rabbits were administered intra-vitreal injections of 5 microg of topotecan. Vitreous, aqueous, and blood samples were collected at pre-defined time points. A validated high-performance liquid chromatography assay was used to quantitate topotecan (lactone and carboxylate) concentrations. Topotecan pharmacokinetic parameters were determined in vitreous, aqueous and plasma using a compartmental analysis. Topotecan lactone concentrations in the vitreous of the injected eye were about 8 ng/mL 48 h after drug administration. The median maximum vitreous, aqueous and plasma total topotecan concentrations (C(max)) were 5.3, 0.68 and 0.21 microg/mL, respectively. The C(max) vitreous/aqueous of treated eyes and the C(max) vitreous/plasma were approximately 8 and 254, respectively. Total topotecan exposure (AUC) in the vitreous of the injected eye was 50 times greater than the total systemic exposure. These findings suggest that intra-vitreal administration of only 5 microg of topotecan reaches significant local levels over an extended period of time while minimizing systemic exposure in the rabbit. Intra-vitreal topotecan administration offers a promising alternative route for enhanced drug exposure in the vitreous humor with potential application for treatment of vitreal seeds in retinoblastoma while avoiding systemic toxicities.

• Authors: Emiliano Buitrago, Christian Höcht, Guillermo Chantada, Adriana Fandiño, Elliot Navo, David H Abramson, Paula Schaiquevich, Guillermo F Bramuglia
• Journal: Experimental eye research (Exp Eye Res) Vol. 91 Issue 1 Pg. 9-14 (Jul 2010) ISSN: 1096-0007 [Electronic] England
• PMID: 20307538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Topotecan

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Aqueous Humor (metabolism)
• Biological Availability
• Chromatography, High Pressure Liquid
• Injections
• Rabbits
• Retinal Neoplasms (drug therapy)
• Retinoblastoma (drug therapy)
• Topotecan (pharmacokinetics, therapeutic use)
• Vitreous Body (metabolism)