title: Pharmacokinetics, lymph node uptake, and mechanistic PK model of near-infrared dye-labeled bevacizumab after IV and SC administration in mice.
abstract: Our objective was to determine the pharmacokinetics, bioavailability and lymph node uptake of the monoclonal antibody bevacizumab, labeled with the near-infrared (IR) dye 800CW, after intravenous (IV) and subcutaneous (SC) administration in mice. Fluorescence imaging and enzyme-linked immunosorbent assay (ELISA) assays were developed and validated to measure the concentration of bevacizumab in plasma. The bevacizumab-IRDye conjugate remained predominantly intact in plasma and in lymph node homogenate samples over a 24-h period, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and size exclusion chromatography. The plasma concentration vs. time plots obtained by fluorescence and ELISA measurements were similar; however, unlike ELISA, fluorescent imaging was only able to quantitate concentrations for 24 h after administration. At a low dose of 0.45 mg/kg, the plasma clearance of bevacizumab was 6.96 mL/h/kg after IV administration; this clearance is higher than that reported after higher doses. Half-lives of bevacizumab after SC and IV administration were 4.6 and 3.9 days, respectively. After SC administration, bevacizumab-IRDye800CW was present in the axillary lymph nodes that drain the SC site; lymph node uptake of bevacizumab-IRDye 800CW was negligible after IV administration. Bevacizumab exhibited complete bioavailability after SC administration. Using a compartmental pharmacokinetic model, the fraction absorbed through the lymphatics after SC administration was estimated to be about 1%. This is the first report evaluating the use of fluorescent imaging to determine the pharmacokinetics, lymphatic uptake, and bioavailability of a near-infrared dye-labeled antibody conjugate.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York 14260, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.forename: Mitalee
authors.initials: M
authors.lastname: Tamhane
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000068258:Bevacizumab; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D019265:Spectroscopy, Near-Infrared / Q000379:methods
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D005456:Fluorescent Dyes; D000068258:Bevacizumab