Pharmacokinetics and Pharmacodynamics of Anti-BR3 Monoclonal Antibody in Mice
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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.
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.
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 (Tmax = 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.
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.
Key WordsB-cell activating factor B-cell activating factor Receptor 3 mathematical modeling pharmacodynamics pharmacokinetics
Acknowledgments and Disclosures
This research was funded, in part, by NIH grant GM57980 (D.E.M.). Dr. Mager has served as a paid consultant to Genentech Inc.
- 12.Halpern WG, Lappin P, Zanardi T, Cai W, Corcoran M, Zhong J, et al. Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic, and toxicologic effects. Toxicol Sci. 2006;91:586–99.PubMedCrossRefGoogle Scholar
- 18.Gaddum JH. The quantitative effects of antagonistic drugs. J Physiol. 1937;89:7P–9.Google Scholar
- 19.Kenakin T. Pharmacologic analysis of drug-receptor interaction. Raven Press. 1993;10:331–73.Google Scholar
- 23.D’Argenio DZ, Schumitzky A, Wang X. ADAPT 5 user’s guide. Los Angeles: Biomedical Simulation Resource; 2009.Google Scholar