Pharmacokinetics and pharmacodynamics of a chimeric/humanized anti-CD3 monoclonal antibody, otelixizumab (TRX4), in subjects with psoriasis and with type 1 diabetes mellitus.
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.
Wiczling
Pawel
P
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 565 Hochstetter Hall, State University of New York at Buffalo, Buffalo, NY 14260, USA.
Rosenzweig
Michael
M
Vaickus
Louis
L
Jusko
William J
WJ
D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002986:Clinical Trials as Topic; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007262:Infusions, Intravenous; D008954:Models, Biological; D011565:Psoriasis / Q000188:drug therapy / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; C550701:otelixizumab