Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2012, 156(4):318-323 | DOI: 10.5507/bp.2011.068

Topotecan vitreous and plasma levels and retinal toxicity after transcorneal intravitreal delivery in healthy albino rabbits: Alternative retinoblastoma treatment

Denisa Darsova^a, Pavel Pochop^a, Jiri Uhlik^b, Eva Klapkova^c, Hundie Tesfaye^c, Daniela Kodetova^d, Jan Lestak^e, Josef Malis^f, Ludek Vajner^b

^a Department of Ophthalmology for Children and Adults, Charles University 2^nd Faculty of Medicine and Motol Hospital, Prague, Czech Republic

^b Department of Histology and Embryology, Charles University 2^nd Faculty of Medicine, Prague

^c Department of Clinical Biochemistry and Pathobiochemistry, Charles University 2^nd Faculty of Medicine and Motol Hospital, Prague

^d Department of Pathology and Molecular Medicine, Charles University 2^nd Faculty of Medicine and Motol Hospital, Prague

^e Department of Ophthalmology, Clinic of Jan Lestak, Prague

^f Department of Paediatric Haematology and Oncology, 2^nd Faculty of Medicine and Motol Hospital, Prague

Aim: To determine intravitreal and plasma concentrations and retinal toxicity after transcorneal intravitreal injection of 1 μg and 2 μg of topotecan (Hycamtin).

Method: 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.

Conclusion: 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.

Keywords: intravitreal drug delivery, intravitreal seeding, periocular injection, retinoblastoma, topotecan

Received: September 29, 2011; Accepted: November 30, 2011; Prepublished online: December 20, 2011; Published: December 12, 2012  Show citation