Wu Benjamin, Joshi Amita, Ren Song, Ng Chee
Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., 1 DNA Way, MS 70, South San Francisco, CA 94080, USA.
J Pharm Sci. 2006 Jun;95(6):1258-68. doi: 10.1002/jps.20475.
muM17 is an anti-mouse CD11a monoclonal antibody (mAb) developed as a surrogate molecule for assessing potential reproductive toxicities of efalizumab, an anti-human CD11a mAb approved for treatment of chronic moderate to severe plaque psoriasis. This article shows the use of a mechanism-based PK/PD model for muM17 to further support the determination of dose equivalency of muM17 in the mouse and efalizumab in humans based on CD11a expression on T-lymphocytes (PD). Patients in clinical studies received 1 mg/kg/week efalizumab subcutaneously for 12 weeks. In the mouse model, a single IV dose of 1 or 10 mg/kg or a single SC dose of 3, 5, or 10 mg/kg muM17 was administered. Drug concentrations and PD were quantitated using ELISA and flow cytometry (FACS) analyses, respectively. The PK/PD model of muM17 in mice was developed and was validated using sparse data from a separate multiple dose PK/PD study. The model was next used to simulate PD profiles with multiple dosing regimens mimicking those of the clinical dose of efalizumab. The model showed that 3 mg/kg/week SC administration of muM17 in mice is the minimum dose that can produce PD effects similar to those produced following 1 mg/kg/week SC of efalizumab in humans.
muM17是一种抗小鼠CD11a单克隆抗体（mAb），作为一种替代分子开发，用于评估依法利珠单抗的潜在生殖毒性。依法利珠单抗是一种已被批准用于治疗慢性中度至重度斑块状银屑病的抗人CD11a mAb。本文展示了基于机制的muM17药代动力学/药效学（PK/PD）模型的应用，以进一步支持基于T淋巴细胞上CD11a表达（药效学）来确定小鼠体内muM17与人用依法利珠单抗的等效剂量。临床研究中的患者接受皮下注射1 mg/kg/周的依法利珠单抗，持续12周。在小鼠模型中，静脉注射单剂量1或10 mg/kg的muMl7，或皮下注射单剂量3、5或10 mg/kg的muM17。分别使用酶联免疫吸附测定（ELISA）和流式细胞术（FACS）分析对药物浓度和药效学进行定量。开发了小鼠体内muM17的PK/PD模型，并使用来自另一项多剂量PK/PD研究的稀疏数据进行了验证。接下来，该模型用于模拟与依法利珠单抗临床剂量相似的多剂量给药方案的药效学特征。该模型表明，在小鼠中皮下注射3 mg/kg/周的muM17是能够产生与人类皮下注射1 mg/kg/周依法利珠单抗相似药效学效应所需的最小剂量。
