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

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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 (r2: 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.

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Abbreviations

CL:

systemic clearance

GFR:

glomerular filtration rate

IgG:

immunoglobulin G

mAb:

monoclonal antibody

STZ:

streptozotocin

UAE:

urinary albumin excretion rate

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by a grant from the Center for Protein Therapeutics.

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Authors and Affiliations

  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

    Frank A. Engler, Bo Zheng & Joseph P. Balthasar

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  1. Frank A. Engler
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  2. Bo Zheng
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  3. Joseph P. Balthasar
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Correspondence to Joseph P. Balthasar.

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Engler, F.A., Zheng, B. & Balthasar, J.P. Investigation of the Influence of Nephropathy on Monoclonal Antibody Disposition: A Pharmacokinetic Study in a Mouse Model of Diabetic Nephropathy. Pharm Res 31, 1185–1193 (2014). https://doi.org/10.1007/s11095-013-1241-y

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  • DOI: https://doi.org/10.1007/s11095-013-1241-y

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