Interspecies pharmacokinetic modeling of subcutaneous absorption of rituximab in mice and rats

Leonid Kagan, Jie Zhao, Donald E. Mager

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Conclusions: Subcutaneous absorption processes show similar trends in rats and mice, although the magnitude differs between species. A mathematical model that combines the absorption of free and bound antibody with presystemic degradation successfully captured rituximab pharmacokinetics in both species, and approaches for sharing and scaling parameters between species were identified.

Purpose: To investigate the effect of dose level and anatomical site of injection on the pharmacokinetics of rituximab in mice, and to evaluate the utility of a pharmacokinetic model for describing interspecies differences in subcutaneous absorption between mice and rats.

Methods: Rituximab serum concentrations were measured following intravenous and subcutaneous administration at the back and abdomen of mice. Several approaches were compared for scaling model parameters from estimated values in rats.

Results: The bioavailability of rituximab following subcutaneous injection was inversely related to the dose level and was dependent on the site of injection in mice. The overall rate of absorption was faster in mice as compared to rats. Subcutaneous absorption profiles were well described using the proposed structural model, in which the total receptor concentration, the affinity of rituximab to the receptor, and the degradation rate constant were assumed to be species independent.

Original languageEnglish (US)
Pages (from-to)3265-3273
Number of pages9
JournalPharmaceutical research
Volume31
Issue number12
DOIs
StatePublished - Dec 2014

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Keywords

  • biotherapeutics absorption
  • interspecies scaling
  • mathematical modeling
  • monoclonal antibodies
  • protein therapeutics

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