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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Pharmacokinetic and Pharmacodynamic Modeling of Serum Etrolizumab and Circulating β7 Receptor Occupancy in Patients With Ulcerative Colitis
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Pharmacokinetic and Pharmacodynamic Modeling of Serum Etrolizumab and Circulating β7 Receptor Occupancy in Patients With Ulcerative Colitis

机译：血清eTrolizumab和循环β7受体患者溃疡性结肠炎患者的药代动力学与药效模型

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Abstract Etrolizumab, a humanized monoclonal antibody, specifically binds to the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected from an etrolizumab phase 1 trial in patients with moderate to severe ulcerative colitis (UC). We developed a mechanism‐based model to simultaneously describe the kinetics of serum etrolizumab concentration and free β7 receptors on circulating intestinal‐homing CD4 + T lymphocytes. Included in the analysis were 38 phase 1 UC patients who received single or 3 monthly doses of etrolizumab intravenously or subcutaneously across a dose range of 0.3 to 10 mg/kg. A quasi–steady‐state target‐mediated drug disposition model was developed to describe the dynamic interaction between serum etrolizumab concentration and free β7 receptors on intestinal‐homing CD4 + T lymphocytes in UC patients. The time profiles of serum etrolizumab and absolute counts of β7 + lymphocytes (expressed as percentage of baseline level) were well described by the quasi–steady‐state target‐mediated drug disposition model. The model was able to characterize the maximum drug occupancy of β7 receptors on intestinal‐homing CD4 + T lymphocytes and the concentration‐dependent duration of occupancy. The 90% effective concentration for etrolizumab to saturate the β7 receptors on intestinal homing CD4 + T cells was 1.3 μg/mL. PK and PD profiles predicted by the model were consistent with observations from a subsequent phase 2 study. In conclusion, an integrated PK/PD model developed in this analysis reasonably described serum etrolizumab PK profiles and the relationship between PK and PD (free β7 receptors on circulating intestinal‐homing CD4 + T lymphocytes) in UC patients.
机译：摘要eTrolizumab，人源化单克隆抗体，特异性结合β7亚β7和αeβ7的β7亚基。从中度至重度溃疡性结肠炎（UC）的患者中，从Etrolizumab期1试验中收集药代动力学（PK）和药效学（PD）数据。我们开发了一种基于机制的模型，同时描述血清肠肠浓度和游离β7受体的动力学在循环肠宿主CD4 + T淋巴细胞上。分析中包括38阶段1 UC患者，其静脉内或皮下接受单次或3剂量的抗萝卜蛋白剂，或皮下横跨0.3-10mg / kg的剂量范围。开发了一种准稳态靶介导的药物处理模型，描述了UC患者肠归巢CD4 + T淋巴细胞上血清Etrolizumab浓度和游离β7受体之间的动态相互作用。通过准稳态靶介导的药物处理模型很好地描述了血清Etrolizuab和绝对计数的β7+淋巴细胞的绝对计数（表达为基线水平的百分比）。该模型能够在肠宿主CD4 + T淋巴细胞上表征β7受体的最大药物占用率和占占占血液的浓度依赖性持续时间。 Etrolizumab的90％有效浓度以使肠归巢CD4 + T细胞饱和β7受体为1.3μg/ ml。模型预测的PK和PD分布与从后续第2阶段研究的观察结果一致。总之，在该分析中开发的集成PK / PD模型合理地描述了UC患者在UC患者中的PK和Pd（自由β7受体对循环肠宿主CD4 + T淋巴细胞的影响）。

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