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

BUITRAGO E; HÖCHT C; CHANTADA G; FANDIÑO A; NAVO E; ABRAMSON DH; SCHAIQUEVICH P; BRAMUGLIA GF

EXPERIMENTAL EYE RESEARCH

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD

Año: 2010 vol. 91 p. 9 - 14

0014-4835

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 mg 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 maximumvitreous, aqueous and plasma total topotecan concentrations (Cmax) were 5.3, 0.68 and 0.21 mg/mL, respectively. The Cmax vitreous/aqueous of treated eyes and the Cmax 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 mg 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.