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Pharm Res. 2014 May;31(5):1185-93. doi: 10.1007/s11095-013-1241-y. Epub 2013 Nov 8.

Investigation of the influence of nephropathy on monoclonal antibody disposition: a pharmacokinetic study in a mouse model of diabetic nephropathy.

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1
Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, Buffalo, New York, 14260, USA.

Abstract

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 < 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.

CONCLUSIONS:

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.

PMID:
24203494
DOI:
10.1007/s11095-013-1241-y
[Indexed for MEDLINE]

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