Pharmacokinetics of Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration: A Population Approach

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Abstract
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 (t1/2) was calculated to be 9 days and the intrinsic systemic elimination t1/2 was calculated to be approximately 2 hours. Following ITV administration, ranibizumab egresses slowly into the systemic circulation, resulting in an apparent serum t1/2 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 steady-state 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.)