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 CD3ε. 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 μg/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 μg/mL for CD4+ T cells and 0.0120 μg/mL for CD8+ T cells. Corresponding values for psoriatic subjects were much lower: 0.000533 for CD4+ T cells and 0.000269 μg/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 μg/mL. Integrated PK/PD models were successfully applied to assess otelixizumab PK and diverse PD responses.