Pharmacokinetics and pharmacodynamics of a chimeric/humanized anti-CD3 monoclonal antibody, otelixizumab (TRX4), in subjects with psoriasis and with type 1 diabetes mellitus.

Abstract

Otelixizumab is an aglycosylated chimeric/humanized monoclonal antibody (mAb) directed to human CD3epsilon. This report describes population pharmacokinetics/pharmacodynamic (PK/PD) modeling of serum otelixizumab concentrations, changes in CD4+ and CD8+ T-cell counts, and modulation and saturation of CD3/T-cell receptors (TCR) (determined by flow cytometry) after IV administration of otelixizumab in subjects with either type 1 diabetes or psoriasis. Otelixizumab PK were monoexponential with Michaelis-Menten elimination. Nonlinearity was manifested at high concentrations (K(m) = 0.968 microg/mL). Lymphocyte dynamics were captured by an indirect response model simplified to direct inhibition. In diabetic subjects, the otelixizumab serum concentration producing a 50% decrease in peripheral blood counts was 0.0187 microg/mL for CD4+ T cells and 0.0120 microg/mL for CD8+ T cells. Corresponding values for psoriatic subjects were much lower: 0.000533 for CD4+ T cells and 0.000269 microg/mL for CD8+ T cells. Total (sum of unbound and otelixizumab-bound) CD3/TCR was approximately equal to unbound CD3/TCR, suggesting that there were few otelixizumab-(CD3/TCR) complexes at the T-cell surface. Down-modulation of CD3/TCR was described by direct inhibition. Otelixizumab concentrations producing 50% reduction in free CD3/TCR sites was similar for diabetes and psoriasis, 0.0144 and 0.0162 microg/mL. Integrated PK/PD models were successfully applied to assess otelixizumab PK and diverse PD responses.

• Authors: Pawel Wiczling, Michael Rosenzweig, Louis Vaickus, William J Jusko
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 50 Issue 5 Pg. 494-506 (May 2010) ISSN: 1552-4604 [Electronic] England
• PMID: 19934031 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• CD3 Complex
• Receptors, Antigen, T-Cell
• otelixizumab

Topics

• Antibodies, Monoclonal (pharmacokinetics, pharmacology)
• Antibodies, Monoclonal, Humanized
• CD3 Complex (immunology)
• CD4 Lymphocyte Count
• CD8-Positive T-Lymphocytes (immunology)
• Clinical Trials as Topic
• Diabetes Mellitus, Type 1 (drug therapy, immunology)
• Flow Cytometry
• Humans
• Infusions, Intravenous
• Models, Biological
• Psoriasis (drug therapy, immunology)
• Receptors, Antigen, T-Cell (immunology)