Topotecan vitreous and plasma levels and retinal toxicity after transcorneal intravitreal delivery in healthy albino rabbits: alternative retinoblastoma treatment.
OBJECTIVE
To determine intravitreal and plasma concentrations and retinal toxicity after transcorneal intravitreal injection of 1 μg and 2 μg of topotecan (Hycamtin).


METHODS
Twelve healthy albino rabbits were included in this in vivo experiment. Six anesthetized albino rabbits received a single transcorneal intravitreal injection of 1 μg (group A) or 2 μg (group B) of topotecan. Vitreous and blood samples were collected until 168 h. Left eyes were treated with the same volume of saline. Plasma and vitreous levels of topotecan were determined by high-performance liquid chromatography. Area under the plasma concentration time curve (AUC) was calculated using trapezoidal rule. Clinical evidence of toxicity was classified into four grades according to anatomical structures. Electroretinograms (ERGs) were recorded.


RESULTS
Time to maximum concentration was observed up to 2 h after drug injection in group A whereas up to 1 h in group B. Low levels of topotecan were detected in plasma in both groups and in the vitreous humor of the contralateral eye in group B. Topotecan levels (mean vitreous AUC in group A 2.55 μg/mL.h and in group B 5.338 μg/mL.h) were detectable up to 6 h in both groups. We observed following structural changes in rabbit eyes: corneal vascularization, cataract, hemophthalmus, choroidal edema and focal retinal atrophy. Abnormal ERGs were obtained.


CONCLUSIONS
Our findings proved that transcorneal intravitreal administration of 1 μg and 2 μg of topotecan results in potentially cytotoxic intraocular concentrations. More studies are needed to establish the safety of topotecan for retinoblastoma in children.
Department of Ophthalmology for Children and Adults, Charles University 2nd Faculty of Medicine and Motol Hospital, Prague, Czech Republic. denisa.darsova@centrum.cz
Denisa
D
Darsova
Pavel
P
Pochop
Jiri
J
Uhlik
Eva
E
Klapkova
Hundie
H
Tesfaye
Daniela
D
Kodetova
Jan
J
Lestak
Josef
J
Malis
Ludek
L
Vajner
D000818:Animals; D011817:Rabbits; D012160:Retina / Q000187:drug effects*; D019572:Retinal Neoplasms / Q000188:drug therapy*; D012175:Retinoblastoma / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage* / Q000032:analysis / Q000097:blood; D019772:Topotecan / Q000008:administration & dosage* / Q000032:analysis / Q000097:blood; D014822:Vitreous Body / Q000737:chemistry*
D059004:Topoisomerase I Inhibitors; D019772:Topotecan