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

• Published in: Investigative ophthalmology & visual science Vol. 54; no. 3; p. 1616
• Main Authors: Xu, Lu, Lu, Tong, Tuomi, Lisa, Jumbe, Nelson, Lu, Jianfeng, Eppler, Steve, Kuebler, Peter, Damico-Beyer, Lisa A., Joshi, Amita
• Format: Journal Article
• Language: English
• Published: United States 05.03.2013
• Subjects: Aged; Antibodies, Monoclonal, Humanized - blood; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - therapeutic use; Clinical Trials as Topic; Female; Half-Life; Humans; Intravitreal Injections; Macular Degeneration - drug therapy; Male; Ranibizumab; Vitreous Body - metabolism
• ISSN: 1552-5783; 1552-5783
• DOI: 10.1167/iovs.12-10260

To characterize ranibizumab pharmacokinetics in patients with AMD. 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. 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. 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.).