Topotecan Pharmacokinetics After Superselective Ophthalmic Artery Infusion And Periocular Administration In The Pig

Abstract

Purpose: : To characterize and compare topotecan pharmacokinetics in the vitreous and plasma of a porcine model after ophthalmic artery infusion (OAI) following super-selective artery catheterization with respect to periocular (POA) administration.

Methods: : The ophthalmic artery was catheterized and 1 mg of topotecan was infused over 30 minutes. After a drug wash-out period, the contralateral eye was used for administering the same dose of topotecan by POA. Serial vitreous specimens were obtained by microdialysis and plasma samples were collected and assayed for topotecan. Pharmacokinetic parameters were calculated and compared between the two routes of topotecan administration.

Results: : Maximum vitreous total concentration (median, range) was significantly higher after OAI (131.8, 112.9-138.7 ng/ml) compared to POA (13.6, 5.5-15.3 ng/ml; p<0.005). The median total topotecan concentration in the vitreous after four hours of OAI was 35.8 (16.9- 42.4) ng/ml compared to 4.2 (1.5- 5.7) ng/ml after POA. Total topotecan vitreous exposure (AUC_vit) after OAI was significantly higher than after POA (299.8, 247.6- 347.2 ng*h/ml and 48.9, 11.8- 63.4 ng*h/ml, respectively; p<0.05). The ratio between vitreous-to-plasma exposures was 29 and 3.4 after OAI and POA, respectively. Systemic exposure for total topotecan was low after both routes of topotecan administration with a trend to be lower after OAI compared to POA (p = 0.54).

Conclusions: : Potentially active levels against retinoblastoma were attained over the whole studied period after OAI in the pig. Super-selective ophthalmic artery infusion resulted in significantly higher vitreous and a trend towards to lower systemic exposure than periocular administration.

Keywords: retinoblastoma • vitreous