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

Abstract

This study employed a mouse model to evaluate the effects of diabetic nephropathy on the pharmacokinetics of 8C2, a murine monoclonal antibody (mAb). Streptozotocin (STZ) was administered to mice to induce diabetic nephropathy (125mg/kg/day × 2). Mice were grouped (n = 8-10) based on time after STZ-treatment (control, 1, 2, 3, 4, or 6weeks), and injected intravenously with 10mg/kg 8C2. Blood samples were collected up to 7days, and 8C2 plasma concentrations were determined via immunoassay. Inulin clearance and urinary albumin excretion rate (UAE) were determined to assess renal function. UAE, inulin clearance, and 8C2 clearance increased significantly following STZ. Comparing control and 6week STZ-treatment groups, UAE and inulin clearance increased from 25.7 ± 3.3 to 99.3 ± 13.7μg/day, and from 421 ± 31 to 584 ± 78μl/min. 8C2 clearance increased from 121 ± 12.5 to 228 ± 61μl/hr/kg (p < 0.01). 8C2 clearance was highly correlated with UAE (r(2): 0.731). Inclusion of UAE as a covariate in population modeling explained significant residual variability in 8C2 clearance. The clearance of 8C2 increased significantly in STZ-treated mice. Population pharmacokinetic modeling suggests that UAE has potential for use in predicting mAb clearance in subjects with diabetic nephropathy, possibly assisting in the individualization of mAb dosing.