Graefe’s Arch Clin Exp Ophthalmol (2004) 242:582–586 LABORATORY INVESTIGATION Sascha Fauser Hubert Kalbacher Nils Alteheld Kan Koizumi Tim U. Krohne Antonia M. Joussen Pharmacokinetics and safety of intravitreally delivered etanercept Received: 8 September 2003 Revised: 11 November 2003 Accepted: 16 February 2004 Published online: 17 March 2004  Springer-Verlag 2004 S. Fauser ( ) ) · N. Alteheld · K. Koizumi · T. U. Krohne · A. M. Joussen Abteilung für Netzhaut- und Glaskörperchirurgie des Zentrums für Augenheilkunde und Zentrum für Molekulare Medizin (ZMMK), Universität zu Köln, Joseph-Stelzmann-Strasse 9, 50931 Cologne, Germany e-mail: sfauser@hgmp.mrc.ac.uk Tel.: +49-221-4787719 Fax: +49-221-4787930 URL: www.retina-cologne.de H. Kalbacher Medizinisch-Naturwissenschaftliches Forschungszentrum, Universität Tübingen, Tübingen, Germany Abstract Background: The anti-in- flammatory drug etanercept may be an effective therapeutic agent in dia- betic retinopathy. In order to further evaluate its potential, the pharmaco- kinetics and safety of this drug after intravitreal delivery were investigat- ed. Methods: After intravitreal ad- ministration of etanercept in rabbits, clinical examination, electroretinog- raphy (ERG), visually evoked poten- tials (VEP) and histology were eval- uated. The pharmacokinetics and distribution of etanercept were ana- lyzed using fluorescence-coupled protein at 0, 2, 4, and 8 weeks after injection in vitreous, retina, and choroid. Results: No adverse effects and signs of toxicity were found. Etanercept showed peak concentra- tions after 4 weeks in the retina and choroid. Conclusions: Intravitreally delivered etanercept is safe and re- sults in high concentrations in the retina and choroid over a long period of time. Introduction Increased leukocyte adhesion to the vascular endothelium is one of the earliest events of inflammation and neovas- cularization. Besides the well-known inflammatory dis- eases such as uveitis in various forms, diseases such as diabetic retinopathy also show signs of inflammation. In diabetic retinopathy increased leukocyte adhesion to the vascular endothelium has been demonstrated in multiple settings [3, 5, 13, 16]. The altered binding results in early blood–retina barrier breakdown, capillary nonperfusion, and endothelial cell injury and death. The adhesion is mediated in part by intercellular adhesion molecule-1 (ICAM-1) [12], which is expressed on endothelial cells and binds to a2-integrins (including CD18) expressed on leukocytes [3, 11]. Various mediators contribute to the up-regulation of endothelial cell and leukocyte adhesion molecules. Tumor necrosis factor a (TNFa) is a proinflammatory cytokine that has been implicated in this process. TNFa expression is upregulated in the extracellular matrix, endothelium, and vessel walls of fibrovascular tissue of eyes with proliferative diabetic retinopathy, and TNFa protein levels are elevated in the vitreous from eyes with this condition [7, 9, 10, 17]. The administration of neutralizing antibodies against ICAM-1 or CD18 in a rat model of diabetic retinopathy markedly reduces leukocyte adhesion and, as a consequence, blood–retina barrier breakdown and endothelial injury [5]. Administration of a soluble DOI 10.1007/s00417-004-0895-x