Pharmacokinetics and pharmacodynamics of anti-BR3 monoclonal antibody in mice.
OBJECTIVE
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.
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 431 Kapoor Hall, Buffalo, New York 14214, USA.
Anshu
A
Marathe
Suhasini
S
Iyer
Zhihua Julia
ZJ
Qiu
Jennifer
J
Visich
Donald E
DE
Mager
D061605:Administration, Intravenous / Q000379:methods; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053264:B-Cell Activating Factor / Q000097:blood / Q000276:immunology / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000276:immunology* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001682:Biological Availability; D007279:Injections, Subcutaneous / Q000379:methods; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological
D000911:Antibodies, Monoclonal; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor