Topotecan Delivery to the Optic Nerve after Ophthalmic Artery Chemosurgery

Abstract

Extraocular retinoblastoma is a major challenge worldwide, especially in developing countries. Current treatment involves the administration of systemic chemotherapy combined with radiation, but there is a clear need for improvement of chemotherapy bioavailability in the optic nerve. Our aim was to study the ophthalmic artery chemosurgery (OAC) local route for drug delivery assessing ocular and optic nerve exposure to chemotherapy and to compare it to exposure after intravenous infusion (IV) of the same dose in an animal model. Topotecan was used as a prototype drug that is active in retinoblastoma and based on the extensive knowledge of its pharmacokinetics in preclinical and clinical settings. Five Landrace pigs received 4mg of topotecan via OAC as performed in retinoblastoma patients. At the end of the infusion, the eyes were enucleated, the optic nerve and retina were dissected, and the vitreous and plasma were separated. After recovery and a wash-out period, the animals received a 30-min IV infusion of topotecan (4 mg). The remaining eye was enucleated and tissues and fluids were separated. All samples were stored until quantitation using HPLC. A significantly higher concentration of topotecan in the optic nerve, vitreous, and retina was obtained in eyes after OAC compared to IV infusion (p<0.05). The median (range) ratio between topotecan concentration attained after OAC to IV infusion in the optic nerve, retina and vitreous was 84(54–668), 143(49–200) and 246(56–687), respectively. However, topotecan systemic exposure after OAC and IV infusion remained comparable (p>0.05). The median optic nerve-to-plasma ratio after OAC and IV was 44 and 0.35, respectively. Topotecan OAC delivery attained an 80-fold higher concentration in the optic nerve compared to the systemic infusion of the same dose with similar plasma concentrations in a swine model. Patients with retinoblastoma extension into the optic nerve may benefit from OAC for tumor burden by increased chemotherapy bioavailability in the optic nerve without increasing systemic exposure or toxicity.