Taich Paula, Requejo Flavio, Asprea Marcelo, Sgroi Mariana, Gobin Pierre, Abramson David H, Chantada Guillermo, Schaiquevich Paula
Clinical Pharmacokinetics Unit, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.
National Scientific and Technical Research Council, CONICET, Buenos Aires, Argentina.
PLoS One. 2016 Mar 9;11(3):e0151343. doi: 10.1371/journal.pone.0151343. eCollection 2016.
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.
眼外视网膜母细胞瘤是全球面临的一项重大挑战，在发展中国家尤为如此。目前的治疗方法包括全身化疗联合放疗，但显然需要提高化疗药物在视神经中的生物利用度。我们的目的是研究眼动脉化学手术（OAC）局部给药途径，评估眼内和视神经对化疗药物的暴露情况，并在动物模型中将其与相同剂量静脉输注（IV）后的暴露情况进行比较。拓扑替康被用作一种在视网膜母细胞瘤中具有活性的原型药物，这是基于其在临床前和临床环境中广泛的药代动力学知识。五只长白猪按照视网膜母细胞瘤患者的操作方式通过OAC接受了4mg拓扑替康。输注结束时，摘除眼球，解剖视神经和视网膜，并分离玻璃体和血浆。恢复并经过洗脱期后，动物接受了30分钟的拓扑替康静脉输注（4mg）。摘除另一只眼睛并分离组织和液体。所有样本均保存至使用高效液相色谱法进行定量分析。与静脉输注相比，OAC后眼中视神经、玻璃体和视网膜中的拓扑替康浓度显著更高（p<0.05）。OAC后视神经、视网膜和玻璃体中拓扑替康浓度与静脉输注后浓度的中位数（范围）比值分别为84（54-668）、143（49-200）和246（56-687）。然而，OAC和静脉输注后拓扑替康的全身暴露情况仍然相当（p>0.05）。OAC和静脉输注后视神经与血浆的中位数比值分别为44和0.35。在猪模型中，与相同剂量的全身输注且血浆浓度相似相比，拓扑替康通过OAC给药在视神经中的浓度高出80倍。视网膜母细胞瘤扩展至视神经的患者可能会因OAC提高了视神经中化疗药物的生物利用度而减轻肿瘤负荷，同时不会增加全身暴露或毒性。
