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.

Quantification of cortical bone loss and repair for therapeutic evaluation in collagen-induced arthritis, by micro-computed tomography and automated image analysis.

OBJECTIVE: Ex vivo and in vivo micro-computed tomography (micro-CT) combined with a novel image analysis algorithm were used to quantify cortical bone loss and periosteal new bone formation for therapeutic evaluation in a murine model of collagen-induced arthritis. METHODS: An automated algorithm was created to locate 5 metatarsophalangeal and 3 metacarpophalangeal joints in 3-dimensional micro-CT images of mouse paws for evaluation of joint cortical bone volume (JCBV) within close proximity of the joints as well as cortical bone mineral density and periosteal new bone formation within the paws. For validation, automated estimates of JCBV were compared with radiographic visual scores (RVS) in 4 treatment groups (n = 9 per group): rat anti-mouse CD11a monoclonal antibody, methotrexate (MTX), anti-CD11a plus MTX, and saline only. In a separate study, serial images of hind limbs were evaluated in 2 treatment groups: murine tumor necrosis factor receptor II-Fc fusion protein (mTNFRII; n = 10) and control antibody (n = 7). RESULTS: Automated estimates of the JCBV were significantly correlated with the RVS (hind paws R = -0.94, front paws R = -0.81, combined R = -0.87). The anti-CD11a group had significantly higher JCBV compared with controls. In the serial study, the automated estimate of JCBV detected significant treatment effects in the mTNFRII-Fc group compared with controls. Cortical bone mineral density was significantly higher in all treatment groups compared with controls. CONCLUSION: Micro-CT combined with a novel image analysis technique (estimation of JCBV) provides a fully automated means to quantify bone destruction in a mouse model of rheumatoid arthritis.