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PURPOSE. To characterize ranibizumab pharmacokinetics in patients with AMD. METHODS.A population approach of nonlinear mixed-effect pharmacokinetic modeling based on concentration-time data from 2993 serum samples from 674 AMD patients enrolled in 5 phase 1 to 3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered biweekly or monthly for up to 24 months. RESULTS.A total of 696 concentration-time records from 229 subjects with one or more measurable total serum ranibizumab concentrations were analyzed. The systemic concentration-time data for ranibizumab were best described by a one-compartment model with first-order absorption into and first-order elimination from the systemic circulation. Vitreous elimination half-life (t 1/2 ) was calculated to be 9 days and the intrinsic systemic elimination t 1/2 was calculated to be approximately 2 hours. Following ITV administration, ranibizumab egresses slowly into the systemic circulation, resulting in an apparent serum t 1/2 of 9 days. Systemic-to-vitreous exposure ratio was estimated to be 1:90,000. With monthly and quarterly ITV regimens, the serum concentrations of ranibizumab at steadystate for both the 0.3 and 0.5 mg/eye dose levels were estimated to be below the range needed to inhibit VEGF-A-induced endothelial cell proliferation in vitro by 50% at all times.CONCLUSIONS. Systemic exposure to ranibizumab after ITV injection was very low due to elimination on reaching systemic circulation from the vitreous. Population pharmacokinetic analysis of data from a representative sample of AMD patients did not identify clinically significant sources or correlates of variability in ranibizumab exposure. (ClinicalTrials.gov numbers, NCT00056836, NCT00056823.) (Invest Ophthalmol Vis

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New MA was detected in 29% of study eyes after 24 months of treatment. Clinically significant BCVA gains were achieved with MA present over 24 months. Baseline subretinal fluid absence, intraretinal cyst presence, and fellow eye atrophy presence were associated with month 24 MA presence. With existing data, the benefits of ranibizumab for neovascular AMD outweighed the risk of MA development over 24 months in HARBOR, although outcomes >2 years were not evaluated.