Treatment of intraocular
retinoblastoma with vitreous seeding is a challenge. Different routes of
chemotherapy administration have been explored in order to attaining pharmacological concentrations into the posterior chamber. Intravitreal
drug injection is a promissing route for maximum bioavailability to the vitreous but it requires a well defined dose for achieving
tumor control while limited toxicity to the retina.
Topotecan proved to be a promising agent for
retinoblastoma treatment due to its pharmacological activity and limited toxicity. High and prolonged concentrations were achieved in the rabbit vitreous after 5 μg of intravitreal
topotecan. However, whether a lower dose could achieve potentially therapeutic levels remained to be determined. Thus, we here study the pharmacokinetics of
topotecan after 0.5 μg and the toxicity profile of intravitreal
topotecan in the rabbit eye as a potential treatment of
retinoblastoma. A cohort of rabbits was used to study
topotecan disposition in the vitreous after a single dose of 0.5 μg of intravitreal
topotecan. In addition, an independent cohort of non-
tumor bearing rabbits was employed to evaluate the clinical and
retinal toxicity after four weekly
injections of two different doses of intravitreal
topotecan (Group A, 5 μg/dose; Group B, 0.5 μg/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 of rabbits (Group C) served as double control (both eyes injected with
normal saline). Animals were weekly evaluated for clinical and hematologic values and ocular evaluations were performed with an inverse ophthalmoscope to establish potential
topotecan toxicity. Weekly controls included
topotecan quantitation in 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 and samples for
retinal histology were obtained. Our results indicate that
topotecan shows non linear pharmacokinetics after a single intravitreal dose in the range of 0.5-5 μg in the rabbit. Vitreous concentration of
lactone topotecan was close to the concentration assumed to be therapeutically active after 5 h of 0.5 μg intravitreal administration. Eyes injected with four weekly doses of
topotecan (0.5 or 5 μg/dose) showed no significant differences in their ERG wave amplitudes and implicit times in comparison with control (p > 0.05). Animals showed no weight,
hair loss or significant changes in hematologic values during the study period. There were no significant histologic damage of the retinas exposed to
topotecan treatments. After intravitreal administration no
topotecan could be detected in plasma during the follow-up period nor in the vitreous of treated and control animals after 1 week of the last injection. The present data shows that four weekly
intravitreal injection of 5 μg of
topotecan is safe for the rabbit eye. Despite multiple
injections of 0.5 μg of
topotecan are also safe to the rabbit eye,
lactone topotecan vitreous concentrations were potentially active only after 5 h of the administration. We postulate promising translation to clinics for
retinoblastoma treatment.