Investigation of the Influence of Protein-Losing Enteropathy on Monoclonal Antibody Pharmacokinetics in Mice

作者: Yujie Yang , Tommy R. Li , Joseph P. Balthasar

DOI: 10.1208/S12248-017-0135-Z

关键词: Protein losing enteropathyBlood proteinsImmunologyColitisMonoclonal antibodyChemistryPopulationAntibodyInflammatory bowel diseasePharmacokineticsPharmacology

摘要: Protein losing enteropathy (PLE), which is characterized by substantial loss of plasma proteins into the gastrointestinal (GI) tract, a complication variety GI diseases, including inflammatory bowel disease. Clinical studies have found that clearance monoclonal antibodies (mAb) often increased in subjects with diseases known to cause PLE; however, direct relationships between PLE and mAb pharmacokinetics not been demonstrated. This study employed murine model colitis examine influence on pharmacokinetics. Mice were given dextran sodium sulfate (DSS, 2% w/v) supplemented tap water as drinking source for 6 days induce PLE. then intravenously injected 8C2, IgG1 mAb. 8C2 concentrations measured up 14 days post injection. Fecal alpha-1-antitrypsin (A1AT) was biomarker DSS-treated mice developed clinically relevant severity. They also showed transient increase decrease exposure. The area under concentration-time curve length (AUC0-14d) reduced from 1368 ± 255 594 ± 224 day μg/ml following DSS treatment (p = 0.001). A quantitative relationship A1AT obtained via population pharmacokinetic modeling. substantially Increased highly correlated fecal clearance, suggesting possible utility mechanistic predict therapeutic antibodies.

参考文章(63)
Katsuyoshi Ishihama, Tomohiko Orii, Shoichiro Fujishima, Hong-Jin Shu, Tadahisa Fukui, Hiroaki Takeda, Yuichi Nakazawa, Sumio Kawata, Significance of rapid turnover proteins in protein-losing gastroenteropathy. Hepato-gastroenterology. ,vol. 50, pp. 1963- 1965 ,(2003)
Chintamaneni P. Choudari, Seamus O'Mahony, Gordon Brydon, Obedy Mwantembe, Anne Ferguson, Gut lavage fluid protein concentrations: objective measures of disease activity in inflammatory bowel disease. Gastroenterology. ,vol. 104, pp. 1064- 1071 ,(1993) , 10.1016/0016-5085(93)90275-H
Thomas A. Waldmann, Warren Strober, Metabolism of Immunoglobulins Progress in allergy. ,vol. 13, pp. 1- 110 ,(1969) , 10.1159/000385919
Xindong Liu, Lilin Ye, Gregory J. Christianson, Jun-Qi Yang, Derry C. Roopenian, Xiaoping Zhu, NF-κB Signaling Regulates Functional Expression of the MHC Class I-Related Neonatal Fc Receptor for IgG via Intronic Binding Sequences Journal of Immunology. ,vol. 179, pp. 2999- 3011 ,(2007) , 10.4049/JIMMUNOL.179.5.2999
Jin Chen, Joseph P. Balthasar, Development and Characterization of High-Affinity Anti-Topotecan IgG and Fab Fragments Pharmaceutical Sciences Encyclopedia. pp. 835- 850 ,(2010) , 10.1002/9780470571224.PSE316
Kazuko Shichijo, Mutsumi Matuu, Yuji Ikeda, Shinji Naito, Masahiro Ito, Ichiro Sekine, Clinicopathologic study of dextran sulfate sodium experimental murine colitis Laboratory Investigation. ,vol. 69, pp. 238- 249 ,(1998) , 10.1016/S0021-5198(19)41298-5
W.L. Beeken, H.J. Busch, D.L. Sylwester, Intestinal protein loss in Crohn's disease. Gastroenterology. ,vol. 62, pp. 207- 215 ,(1972) , 10.1016/S0016-5085(72)80171-9
Isao Okayasu, Shigeru Hatakeyama, Masahiro Yamada, Toshifumi Ohkusa, Yoshio Inagaki, Rintaro Nakaya, A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice Gastroenterology. ,vol. 98, pp. 694- 702 ,(1990) , 10.1016/0016-5085(90)90290-H
Ryan J Hansen, Joseph P Balthasar, None, Intravenous Immunoglobulin Mediates an Increase in Anti-Platelet Antibody Clearance via the FcRn Receptor Thrombosis and Haemostasis. ,vol. 88, pp. 898- 899 ,(2002) , 10.1055/S-0037-1613331