Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma.

BUITRAGO EMILIANO; DEL SOLE MARIA JOSE; TORBIDONI ANA VANESA; FANDIÑO ADRIANA; ASPREA MARCELO; CROXATO OSCAR; CHANTADA GUILLERMO; BRAMUGLIA GUILLERMO; SCHAIQUEVICH PAULA

EXPERIMENTAL EYE RESEARCH

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2013 vol. 108 p. 103 - 109

0014-4835

Treatment of intraocular retinoblastoma with vitreous seeding is a challenge. Different routes of chemotherapyadministration have been explored in order to attaining pharmacological concentrations intothe posterior chamber. Intravitreal drug injection is a promissing route for maximum bioavailability tothe vitreous but it requires a well defined dose for achieving tumor control while limited toxicity to theretina. Topotecan proved to be a promising agent for retinoblastoma treatment due to its pharmacologicalactivity and limited toxicity. High and prolonged concentrations were achieved in the rabbitvitreous after 5 mg of intravitreal topotecan. However, whether a lower dose could achieve potentiallytherapeutic levels remained to be determined. Thus, we here study the pharmacokinetics of topotecanafter 0.5 mg and the toxicity profile of intravitreal topotecan in the rabbit eye as a potential treatment ofretinoblastoma. A cohort of rabbits was used to study topotecan disposition in the vitreous after a singledose of 0.5 mg of intravitreal topotecan. In addition, an independent cohort of non-tumor bearing rabbitswas employed to evaluate the clinical and retinal toxicity after four weekly injections of two differentdoses of intravitreal topotecan (Group A, 5 mg/dose; Group B, 0.5 mg/dose) to the right eye of each animal.The same volume (0.1 ml) of normal saline was administered to the left eye as control. A third group ofrabbits (Group C) served as double control (both eyes injected with normal saline). Animals were weeklyevaluated for clinical and hematologic values and ocular evaluations were performed with an inverseophthalmoscope to establish potential topotecan toxicity. Weekly controls included topotecan quantitationin plasma of all rabbits. Electroretinograms (ERGs) were recorded before and after topotecan doses.One week after the last injection, topotecan concentrations were measured in vitreous of all eyes andsamples for retinal histology were obtained. Our results indicate that topotecan shows non linearpharmacokinetics after a single intravitreal dose in the range of 0.5e5 mg in the rabbit. Vitreousconcentration of lactone topotecan was close to the concentration assumed to be therapeuticallyactive after 5 h of 0.5 mg intravitreal administration. Eyes injected with four weekly doses oftopotecan (0.5 or 5 mg/dose) showed no significant differences in their ERG wave amplitudes andimplicit times in comparison with control (p > 0.05). Animals showed no weight, hair loss orsignificant changes in hematologic values during the study period. There were no significant histologicdamage of the retinas exposed to topotecan treatments. After intravitreal administration no topotecancould be detected in plasma during the follow-up period nor in the vitreous of treated and controlanimals after 1 week of the last injection. The present data shows that four weekly intravitreal injectionof 5 mg of topotecan is safe for the rabbit eye. Despite multiple injections of 0.5 mg of topotecan are alsosafe to the rabbit eye, lactone topotecan vitreous concentrations were potentially active only after 5 h ofthe administration. We postulate promising translation to clinics for retinoblastoma treatment.