The application of mechanism-based PK/PD modeling in pharmacodynamic-based dose selection of muM17, a surrogate monoclonal antibody for efalizumab.

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. (c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association