Investigation of the Influence of Nephropathy on Monoclonal Antibody Disposition: A Pharmacokinetic Study in a Mouse Model of Diabetic Nephropathy

• Published in: Pharmaceutical research 2014-05, Vol.31 (5), p.1185-1193
• Main Authors: Engler, Frank A., Zheng, Bo, Balthasar, Joseph P.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacokinetics; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Diabetic Nephropathies - immunology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - physiopathology; Diabetic neuropathy; Disease Models, Animal; Glomerular Filtration Rate; Inulin - metabolism; Kinetics; Male; Medical Law; Mice; Monoclonal antibodies; Nephrology; Pharmacology; Pharmacology/Toxicology; Pharmacy; Research Paper; Rodents; Streptozocin
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-1241-y

Purpose This study employed a mouse model to evaluate the effects of diabetic nephropathy on the pharmacokinetics of 8C2, a murine monoclonal antibody (mAb). Methods Streptozotocin (STZ) was administered to mice to induce diabetic nephropathy (125 mg/kg/day × 2). Mice were grouped ( n  = 8–10) based on time after STZ-treatment (control, 1, 2, 3, 4, or 6 weeks), and injected intravenously with 10 mg/kg 8C2. Blood samples were collected up to 7 days, and 8C2 plasma concentrations were determined via immunoassay. Inulin clearance and urinary albumin excretion rate (UAE) were determined to assess renal function. Results UAE, inulin clearance, and 8C2 clearance increased significantly following STZ. Comparing control and 6 week STZ-treatment groups, UAE and inulin clearance increased from 25.7 ± 3.3 to 99.3 ± 13.7 μg/day, and from 421 ± 31 to 584 ± 78 μl/min. 8C2 clearance increased from 121 ± 12.5 to 228 ± 61 μl/hr/kg ( p