Pharmacokinetics and pharmacodynamics of anti-BR3 monoclonal antibody in mice

Purpose: To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a monoclonal antibody directed against the B-cell activating factor (BAFF) receptor 3 (BR3), following intravenous (IV) and subcutaneous (SC) administration in mice. Methods: Single IV doses of 0.2, 2.0 and 20 mg/kg and a single SC injection of 20 mg/kg of anti-BR3 antibody was administered to mice. Serum drug and BAFF concentrations and splenic B-cell concentrations were measured at various time points. Pooled PK profiles were described by a two-compartmental model with time-dependent nonlinear elimination, and BAFF profiles were defined by an indirect response model. Fractional receptor occupancy served as the driving function for a competitive reversible antagonism model to characterize B-cell dynamics. Results: Noncompartmental analysis revealed a decrease in drug clearance (31.3 to 7.93 mL/day/kg) with increasing IV doses. The SC dose exhibited slow absorption (T_max∈=∈2 days) and complete bioavailability. All doses resulted in a dose-dependent increase in BAFF concentrations and decrease in B-cell counts. The proposed model reasonably captured complex PK/PD profiles of anti-BR3 antibody after IV and SC administration. Conclusions: A mechanistic model was developed that describes the reversible competition between anti-BR3 antibody and BAFF for BR3 receptors and its influence on B-cell pharmacodynamics.