Clinical Pharmacokinetics of Ranibizumab (LucentisTM) in Subjects With AMD

Abstract

Abstract: : Purpose: Ranibizumab, a humanized monoclonal antibody fragment targeting VEGF, is currently in Phase III clinical trials for the treatment of neovascular age–related macular degeneration (AMD). In rabbits and cynomolgus monkeys, following intravitreal (ITV) administration, serum ranibizumab concentrations were greater than 1000 fold lower than in the vitreous. In animals the serum half–life was ∼3 days and was comparable to the vitreous half–life. The present analysis was conducted to evaluate the serum pharmacokinetics of ranibizumab in patients with AMD included in three Phase I and I/II clinical trials. Methods: Data from subjects who received unilateral ranibizumab doses ranging from 50 to 2000 µg, and a frequency of administration ranging from a single dose to dosing every 2 and 4 weeks (n=120 patients), were included in the analysis. Serum samples were collected at several times following ITV dosing and ranibizumab concentrations were measured using a homogenous electrochemiluminescent immunoassay with a limit of sensitivity of 0.300 ng/mL. Results: Following administration of the first 300 µg/eye monthly ITV dose, mean serum ranibizumab concentrations were less than 0.300 ng/mL in ∼73% of the subjects 1 hour after dosing; in subjects where ranibizumab concentrations were quantifiable, mean (+sd) concentrations were 1.01 (1.35) ng/mL. Twenty–eight days after the first administration, serum ranibizumab concentrations were less than 0.300 ng/mL in 96% of the patients (n=52). With monthly administration of 300 or 500 µg/eye, ranibizumab serum concentrations were lower than the Kd (in vitro affinity constant, <10 ng/mL by BiaCore) of ranibizumab for VEGF. When ranibizumab was dosed every 2 weeks (n=9), dose–normalized serum concentrations appear to reach a plateau after three doses (6 weeks). Conclusions: In subjects with AMD, ranibizumab systemic exposure was negligible following ITV administration of 300 or 500 µg once monthly.

Keywords: age-related macular degeneration • pharmacology • retina