Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration.
OBJECTIVE
Ranibizumab (rhuFab V2; Lucentis, Genentech, South San Francisco, CA) is a humanized monoclonal antibody fragment designed to bind all forms of VEGF, thereby blocking vessel permeability and angiogenesis in neovascular age-related macular degeneration. This study evaluated the pharmacokinetic (PK) and serum bioavailability of ranibizumab after a single intravitreal (ITV) or intravenous (IV) dose in cynomolgus monkeys.


METHODS
Monkeys received ranibizumab as either a bilateral ITV dose (500 or 2000 microg/eye; n = 6/group) or a single IV dose (1000 or 4000 microg/animal; n = 4/group). After ITV administration, ranibizumab concentrations were measured in several ocular compartments and in serum for 10 days and, after IV administration, for 48 hours. Pharmacokinetic parameters were estimated by compartmental and noncompartmental methods.


RESULTS
Ranibizumab cleared in parallel from all ocular compartments, with a terminal half-life of approximately 3 days. It distributed rapidly to the retina (6-24 hours), and concentrations were approximately one third that in the vitreous. After ITV injection, bioavailability (F) was 50% to 60%. Serum concentrations were very low, reflecting wider distribution and faster clearance when ranibizumab reached the serum. After IV administration, the terminal half-life was approximately 0.5 day.


CONCLUSIONS
This study demonstrates that ranibizumab has a PK profile that is favorable for its clinical use in treating neovascular AMD by monthly ITV injection.
Gaudreault
Jacques
J
Department of Pharmacokinetic, Genentech Inc., South San Francisco, CA 94080, USA. jacques@gene.com
Fei
David
D
Rusit
Jeriza
J
Suboc
Pamela
P
Shiu
Vanessa
V
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D001082:Aqueous Humor / Q000378:metabolism*; D019540:Area Under Curve; D001682:Biological Availability; D004353:Drug Evaluation, Preclinical; D005260:Female; D006207:Half-Life; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007267:Injections; D008252:Macaca fascicularis; D008297:Male; D000069579:Ranibizumab; D011993:Recombinant Fusion Proteins; D012160:Retina / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab