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Emiliano F. Buitrago, Ana Torbidoni, Adriana Fandino, Marcelo Asprea, Sergio Sierre, Flavio Requejo, David H. Abramson, Guillermo Bramuglia, Guillermo L. Chantada, Paula Schaiquevich; Superselective Intra-arterial Chemotherapy For Retinoblastoma Treatment: Comparative Pharmacokinetics Of Topotecan And Melphalan In The Swine Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1880.
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Vitreous seeding remains the greatest obstacle to cure intraocular retinoblastoma and new treatment alternatives are needed in the clinic. The aim of this work was to characterize and compare vitreous and plasma pharmacokinetics of Topotecan and Melphalan, after super-selective ophthalmic artery infusion (SSOAI) in a swine model.
Topotecan (1 mg) or Melphalan (7 mg) were administered by SSOAI over 30 minutes in two groups of 9 pigs, respectively. Serial vitreous samples were obtained by microdialysis and plasma samples were collected over 4 hours and assayed for both drugs. Plasma and vitreous samples were measured by HPLC and pharmacokinetic parameters were calculated for each drug. The 50 % inhibitory concentration (IC50) was estimated in vitro for both drugs from retinoblastoma cell line Y79.
The maximum median concentration of vitreous (Cmax) obtained was 288 nM (range 247-303) for Topotecan and 650 nM for Melphalan (range 160-1360). The ratio between the vitreous and plasma Cmax and area under the curve (AUC) 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 µM and AUC: 0.042 and 0.4 µM for Topotecan and Melphalan, respectively). The IC50 obtained were 10 nM and 1000 nM for Topotecan and Melphalan, respectively.
Both drugs can achieve cytotoxic levels in the vitreous after intra-arterial administration with low systemic exposure. However, Topotecan penetration to the vitreous is more efficient.
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