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Pharmaceutical Research

, Volume 29, Issue 11, pp 3180–3187 | Cite as

Pharmacokinetics and Pharmacodynamics of Anti-BR3 Monoclonal Antibody in Mice

  • Anshu Marathe
  • Suhasini Iyer
  • Zhihua Julia Qiu
  • Jennifer Visich
  • Donald E. Mager
Research Paper

Abstract

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 (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.

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.

Key Words

B-cell activating factor B-cell activating factor Receptor 3 mathematical modeling pharmacodynamics pharmacokinetics 

Notes

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.

Supplementary material

11095_2012_813_MOESM1_ESM.doc (345 kb)
ESM 1 (DOC 345 kb)

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Anshu Marathe
    • 1
  • Suhasini Iyer
    • 2
  • Zhihua Julia Qiu
    • 2
  • Jennifer Visich
    • 2
  • Donald E. Mager
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New YorkBuffaloUSA
  2. 2.Genentech Inc.South San FranciscoUSA

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