Vitreous Levels of Bevacizumab and Vascular Endothelial Growth Factor-A in Patients with Choroidal Neovascularization.

Vitreous Levels of Bevacizumab and Vascular Endothelial Growth Factor-A in Patients with Choroidal Neovascularization.
Zhu Q, Ziemssen F, Henke-Fahle S, Tatar O, Szurman P, Aisenbrey S, Schneiderhan-Marra N, Xu X, Bevacizumab T, Grisanti S
Ophthalmology. 2008 Oct;115(10):1750-5, 1755.e1. doi: 10.1016/j.ophtha.2008.04.023. Epub 2008 Aug 16.

PURPOSE:
To investigate the vitreous levels of bevacizumab and vascular endothelial growth factor-A (VEGF-A) after intravitreal injection of the drug in patients with choroidal neovascularization (CNV).

DESIGN:
Interventional case series.

PARTICIPANTS:
Eleven eyes of 11 patients with submacular hemorrhage and CNV due to age-related macular degeneration (n = 10) or angioid streaks (n = 1).

METHODS:
All patients were treatment naïve except for a single dose of intravitreal injection of bevacizumab (1.25 mg/50 muL dose) and subsequent vitrectomy after various intervals (1-101 days) because of active and progressive lesion. Intravitreal free bevacizumab and VEGF-A levels were measured using enzyme-linked immunosorbent assay and microsphere-based immunoassay, respectively. Vitreous VEGF-A isoforms were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting.

MAIN OUTCOME MEASURES:
Intravitreal bevacizumab and VEGF-A levels were measured and pharmacokinetic parameters were calculated.

RESULTS:
Pharmacokinetics of intravitreal bevacizumab followed a 2-compartment model with initial and terminal half-lives of 0.5 and 6.7 days, respectively. Bevacizumab could be detected in all cases, ranging from 2.63 ng/ml to 165 microg/ml. The peak concentration was observed on the second day after intravitreal bevacizumab injection. Vitreous free VEGF-A levels ranged from 0.2 to 33.9 pg/ml and showed a negative correlation with the bevacizumab concentration (P<0.001; r = -0.955) and a positive correlation with time (P<0.001; r = 0.964). However, the percentage expression of VEGF-A(165) exhibited a positive correlation with the bevacizumab concentration (P = 0.032, r = 0.645) and a negative correlation with time (P = 0.007, r = -0.755). A time-dependent increase was found for the percentage expression of VEGF-A(189) (P = 0.023, r = 0.673). Neither bevacizumab- nor time-related alterations were found for VEGF-A(121).

CONCLUSIONS:
Based on pharmacokinetics, the interval of 6-7 weeks would be appropriate for efficacy, although clinical trials should guide dosing recommendations. Vitreous levels of free VEGF-A showed a negative correlation with the bevacizumab concentration, which confirmed the in vivo binding affinity of bevacizumab to VEGF-A. The analysis of the VEGF-A isoforms suggests differences of interaction between bevacizumab and individual VEGF-A isoforms.