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Lisa Tuomi, Yi Zhang, Jennifer E. Visich; Pharmacokinetics (PK) Of Intravitreal Ranibizumab (RBZ) In Patients With Neovascular Age-related Macular Degeneration (AMD), Retinal Vein Occlusion (RVO), And Diabetic Macular Edema (DMD). Invest. Ophthalmol. Vis. Sci. 2012;53(14):4178.
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To characterize the systemic PK of RBZ in patients with AMD, RVO and DME.
Data from 1696 samples were used in the PK analysis: AMD n=674 (RBZ 0.3-2.0 mg/eye, q4w or pro re nata ), RVO n=520 (RBZ 0.3 or 0.5 mg/eye, q4w) and DME n=502 (RBZ 0.3 or 0.5 mg/eye, q4w). Tested covariates included baseline demographics, metabolic indicators, ocular lesion characteristics, and concomitant treatments. Data were analyzed using the nonlinear mixed-effects modeling program.
A 1-compartment model with first-order absorption into and first-order elimination from the systemic circulation best described the PK of RBZ in AMD, RVO, and DME. Clinically significant PK covariates were not identified. The estimated intrinsic serum elimination half-life (t1/2) of RBZ is only 2 hours. However, following intravitreal administration RBZ egresses slowly into the systemic circulation resulting in a predicted vitreous t1/2 of 9 days and an apparent serum t1/2 of 9 days, The observed systemic concentrations of RBZ in AMD, RVO and DME were at all times well below the IC50 for vascular endothelial growth factor A (VEGF)-induced endothelial cell proliferation in vitro (Figure). The systemic-to-vitreous exposure ratio of RBZ was estimated to be 1:90,000.
The systemic PK of RBZ following intravitreal administration was similar in AMD, RVO and DME patients. Serum RBZ concentrations were at all times below the levels required to inhibit VEGF function in vitro. None of the tested demographic or clinical covariates had a clinically significant effect on RBZ PK.
http://www.clinicaltrials.gov NCT00056836, NCT00061594, NCT00056823, NCT00473330, NCT00473382
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