COMPARATIVE PHARMACOKINETICS OF TOPOTECAN AND MELPHALAN AFTER INTRA-ARTERIAL ADMINISTRATIONS IN THE SWINE MODEL

PAULA SCHAIQUEVICH, PHD, EMILIANO BUITRAGO, BSC, ANA TORBIDONI PHD, ALEJANDRO CECILIANO, MD, ADRIANA FANDINO, MD, JAVIER OPEZZO, PHD, MARCELO ASPREA, DVM, SERGIO SIERRE, MD, FLAVIO REQUEJO, DAVID H. ABRAMSON

Congreso; ICOO 2011 - Biennial Meeting of the International Society of Ocular Oncology; 2011

Purpose. To compare the vitreous and plasma pharmacokinetics of topotecan and melphalan after ophthalmic artery infusion (OAI) following super-selective artery catheterization. Methods. The ophthalmic artery of 8 Landrace pigs was super-selectively catheterized and 1 mg of topotecan in one group and 7 mg of melphalan in the other group were infused over 30 minutes. Serial vitreous specimens were obtained by microdialysis with simultaneous plasma samples. Drug levels were measured by HPLC and pharmacokinetic analysis was carried out with the obtained data. IC50 for each drug were estimated in vitro from retinoblastoma cell line Y79. Results. Maximum median vitreous (Cmax) topotecan concentration in the vitreous was 288 nM, (range 247-303) and that of melphalan 650 nM, (range 160-1360). The ratio between the vitreous and plasma Cmax and area under the curve were 15.4 versus 3.4 and 29 versus 3.2 for topotecan and melphalan respectively. Systemic exposure was low for both drugs (median plasma Cmax: 0.018 and 0.2 uM for topotecan and melphalan respectively). The IC50 for topotecan was 10 nM and for melphalan 1000 nM. Topotecan levels higher than the IC50 were detected for up to 4 hours. Conclusions. Super-selective OAI resulted in vitreous concentrations of topotecan that exceeds the IC50, while melphalan levels are slightly below that range. Topotecan vitreous/plasma concentration is almost 10 times higher than of melphalan.