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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Population pharmacokinetics and pharmacodynamics of the anti-CD11a antibody hu1124 in human subjects with psoriasis.
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Population pharmacokinetics and pharmacodynamics of the anti-CD11a antibody hu1124 in human subjects with psoriasis.

机译：抗CD11a抗体hu1124在牛皮癣患者体内的群体药代动力学和药效学。

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The pharmacokinetics of hu1124, a human anti-CD11a antibody, were investigated in human subjects with psoriasis. CD11a is a subunit of LFA-1, a cell surface molecule involved in T cell mediated immune responses. Subjects received a single dose of 0.03, 0.1, 0.3, 0.6, 1, 2, 3, or 10 mg/kg of hu1124 intravenously over 1-3 hr. Blood samples were collected at selected times from 60 min to 72 days after administration. Plasma samples were assayed for hu1124 by ELISA, and pharmacokinetic analyses were performed on the drug plasma concentrations. As the dose of hu1124 was increased, the clearance decreased from 322 ml/day per kg at 0.1 mg/kg to 6.6 ml/day per kg at 10 mg/kg of hu1124. The plasma hu1124 concentration-time profile suggested that the clearance of hu1124 was saturable above 10 micrograms/ml. In addition, treatment with hu1124 caused a rapid reduction in the level of CD11a expression on CD3-positive lymphocytes (T cells) to about 25% of pretreatment levels. Regardless of the hu1124 dose administered, cell surface CD11a remained at this reduced level as long as hu1124 was detectable (> 0.025 microgram/ml) in the plasma. When hu1124 levels fell below 3 micrograms/ml, the drug was rapidly cleared from the circulation and expression of CD11a returned to normal within 7-10 days thereafter. In vitro, half-maximal binding of hu1124 to lymphocytes was achieved at about 0.1 microgram/ml and saturation required more than 10 micrograms/ml. One of the receptor-mediated pharmacokinetic/pharmacodynamic models which was developed describes the dynamic interaction of hu1124 binding to CD11a, resulting in the removal of hu1124 from the circulation and reduction of cell surface CD11a. The model accounts for the continually changing number of CD11a molecules available for removing hu1124 from the circulation based on prior exposure of cells expressing CD11a to hu1124. In addition, the model also accounts for saturation of CD11a molecules by hu1124 at drug concentrations of approximately 10 micrograms/ml, thereby reducing the clearance rate of hu1124 with increasing dose.
机译：对人类牛皮癣的人类受试者hu1124的药代动力学进行了研究。 CD11a是LFA-1的亚基，LFA-1是参与T细胞介导的免疫反应的细胞表面分子。受试者在1-3小时内静脉内接受0.03、0.1、0.3、0.6、1、2、3或10 mg / kg hu1124的单剂量。在给药后60分钟至72天的选定时间收集血液样品。通过ELISA测定血浆样品中的hu1124，并对药物血浆浓度进行药代动力学分析。随着hu1124剂量的增加，清除率从0.1 mg / kg时的322 ml /天/ kg降至10 mg / kg hu1124时的6.6 ml /天/ kg。血浆hu1124浓度-时间曲线表明hu1124的清除率在10微克/毫升以上是可饱和的。此外，使用hu1124进行治疗会使CD3阳性淋巴细胞（T细胞）上的CD11a表达水平迅速降低至预处理水平的约25％。无论所施用的hu1124剂量如何，只要在血浆中可检测到hu1124（> 0.025微克/毫升），细胞表面CD11a均保持在此降低水平。当hu1124水平降至3微克/毫升以下时，该药物迅速从循环中清除，此后CD11a的表达恢复正常。在体外，hu1124与淋巴细胞的半数最大结合量约为0.1微克/毫升，饱和度需要大于10微克/毫升。已开发的一种受体介导的药代动力学/药效学模型之一描述了hu1124与CD11a结合的动态相互作用，从而导致hu1124从循环中去除并减少了细胞表面CD11a。该模型说明了先前表达CD11a的细胞暴露于hu1124的情况下，可用于从循环中去除hu1124的CD11a分子的数量不断变化。此外，该模型还考虑了在大约10微克/ ml的药物浓度下hu1124会使CD11a分子饱和，从而随着剂量的增加而降低hu1124的清除率。

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