Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 452 Kapoor Hall, Buffalo, NY, 14214-8033, USA.
AAPS J. 2017 Nov;19(6):1791-1803. doi: 10.1208/s12248-017-0135-z. Epub 2017 Aug 28.
Protein losing enteropathy (PLE), which is characterized by substantial loss of plasma proteins into the gastrointestinal (GI) tract, is a complication of a variety of GI diseases, including inflammatory bowel disease. Clinical studies have found that the clearance of monoclonal antibodies (mAb) is often increased in subjects with diseases known to cause PLE; however, direct relationships between PLE and mAb pharmacokinetics have not been demonstrated. This study employed a murine model of colitis to examine the influence of PLE on mAb pharmacokinetics. Mice were given dextran sodium sulfate (DSS, 2% w/v) supplemented tap water as drinking source for 6 days to induce colitis and PLE. Mice were then intravenously injected with 8C2, a murine IgG1 mAb. 8C2 plasma concentrations were measured up to 14 days post injection. Fecal alpha-1-antitrypsin (A1AT) clearance was measured as biomarker for PLE. DSS-treated mice developed PLE of clinically relevant severity. They also showed a transient increase in 8C2 plasma clearance and a decrease in 8C2 plasma exposure. The area under the 8C2 plasma concentration-time curve for the length of the study (AUC) reduced from 1368 ± 255 to 594 ± 224 day μg/ml following DSS treatment (p = 0.001). A quantitative relationship between A1AT clearance and 8C2 clearance was obtained via population pharmacokinetic modeling. DSS treatment substantially increased 8C2 clearance and reduced 8C2 exposure. Increased mAb plasma clearance was highly correlated with A1AT fecal clearance, suggesting the possible utility of A1AT fecal clearance as a mechanistic biomarker to predict the pharmacokinetics of therapeutic antibodies.
蛋白丢失性肠病（PLE）的特征是大量血浆蛋白丢失到胃肠道（GI）中，是多种 GI 疾病的并发症，包括炎症性肠病。临床研究发现，在已知会引起 PLE 的疾病患者中，单克隆抗体（mAb）的清除率常常增加；然而，PLE 与 mAb 药代动力学之间的直接关系尚未得到证明。本研究采用结肠炎小鼠模型研究 PLE 对 mAb 药代动力学的影响。小鼠给予葡聚糖硫酸钠（DSS，2%w/v）补充自来水作为饮水源，连续 6 天诱导结肠炎和 PLE。然后，小鼠静脉注射 8C2，一种鼠 IgG1 mAb。在注射后 14 天内测量 8C2 的血浆浓度。粪便α-1-抗胰蛋白酶（A1AT）清除率被用作 PLE 的生物标志物。DSS 处理的小鼠出现了具有临床相关严重程度的 PLE。它们还显示 8C2 血浆清除率短暂增加和 8C2 血浆暴露减少。在研究期间（AUC）的 8C2 血浆浓度-时间曲线下面积（AUC）从 1368±255 减少到 DSS 处理后的 594±224 天μg/ml（p=0.001）。通过群体药代动力学建模获得了 A1AT 清除率与 8C2 清除率之间的定量关系。DSS 处理显著增加了 8C2 的清除率并降低了 8C2 的暴露。增加的 mAb 血浆清除率与 A1AT 粪便清除率高度相关，表明 A1AT 粪便清除率可能作为预测治疗性抗体药代动力学的机制生物标志物具有一定的应用价值。
