Preclinical Pharmacokinetics of Ranibizumab (rhuFabV2) after a Single Intravitreal Administration

TLDR

Ranibizumab is a humanized monoclonal antibody fragment that binds all VEGF isoforms to inhibit vessel permeability and angiogenesis in neovascular age‑related macular degeneration. This study evaluated the pharmacokinetics and serum bioavailability of ranibizumab after a single intravitreal or intravenous dose in cynomolgus monkeys. The authors measured ranibizumab concentrations in ocular compartments and serum for 10 days after intravitreal injection and 48 hours after intravenous injection, estimating PK parameters with compartmental and non‑compartmental methods. Ranibizumab reached the retina within 6–24 h, achieving about one‑third the vitreous concentration, had 50–60 % intravitreal bioavailability, low serum levels, a 0.5‑day terminal half‑life after IV dosing, and a 3‑day ocular half‑life, supporting its favorable PK for monthly intravitreal use in neovascular AMD.

Abstract

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.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.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.This study demonstrates that ranibizumab has a PK profile that is favorable for its clinical use in treating neovascular AMD by monthly ITV injection.