作者: Yujie Yang , Tommy R. Li , Joseph P. Balthasar
DOI: 10.1208/S12248-017-0135-Z
关键词: Protein losing enteropathy 、 Blood proteins 、 Immunology 、 Colitis 、 Monoclonal antibody 、 Chemistry 、 Population 、 Antibody 、 Inflammatory bowel disease 、 Pharmacokinetics 、 Pharmacology
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.