Pharmacokinetics and Pharmacodynamics of Anti-CD3 Monoclonal Antibody, Otelixizumab, in Subjects with Diabetes and Psoriasis
Paweł Wiczling (1), Michael Rosenzweig (2), Louis Vaickus (2), and William J. Jusko (3)
(1) Department of Biopharmaceutics and Pharmacokinetics, Medical University of Gdansk, Poland; (2) Tolerx, Inc., USA; (3) School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, USA
Objectives: Otelixizumab, a targeted T cell immunomodulator, is a monoclonal antibody directed against the CD3e part of the T-cell receptor complex (CD3/TCR). Otelixizumab administration causes rapid transient redistribution of lymphocytes from blood and down-modulation of CD3/TCR from the T cell surface. Additionally, if the T cell modulation is of sufficient duration these signals induce the up-regulation of T regulatory cells which may lead to long-term immunologic remission. These observed effects of otelixizumab are promising for treatment of various disorders, such as type 1 diabetes, psoriasis, or other T cell mediated autoimmune diseases. This study describes a population pharmacokinetic (PK) model to account for serum otelixizumab concentrations following intravenous administration. It also characterizes the pharmacodynamics (PD) of otelixizumab effects on the absolute counts of CD4+ and CD8+ T cells and on the modulation and saturation of CD3/TCR receptors. The last were determined based on quantitative flow cytometry assays.
Methods: Population nonlinear mixed-effect modeling was done using NONMEM. Data was obtained from three clinical trials involving subjects with diabetes and psoriasis. Total otelixizumab doses ranged from 0.3 mg to 64 mg. The diabetes subjects in Study I received a first dose of 24 or 8 mg, followed by 8 mg doses per day for 5 consecutive days. The psoriasis subjects in Study II received a single dose of 1, 2 or 4 mg. The diabetes subjects in Study III received doses ranging from 0.1 to 0.75 mg per day for 3 to 8 consecutive days.
Results: The one-compartment model with Michaelis-Menten elimination characterized otelixizumab PK. Nonlinearity was manifested at high concentrations (Km = 1.06 µg/ml). For low doses, such as for Study III, the PK was linear with a t1/2 of 0.52 day. The Vd of otelixizumab was 12.8 L suggesting distribution outside the plasma. Lymphocyte dynamics were captured by an indirect response model simplified to the direct inhibitory effect. The initial lymphocyte count was in the normal range of and decreased after otelixizumab administration. In diabetes a 50% decrease in pretreatment CD4+ and CD8+ counts was achieved at otelixizumab concentrations IC50,CD4,D = 0.0220 µg/ml and IC50,CD8,D = 0.0133 µg/ml. The corresponding values for psoriasis were lower: IC50,CD4,P = 0.000670 µg/ml and IC50,CD8,P = 0.000306 µg/ml. In both cases the values of IC50 indicate that low otelixizumab concentrations are effective at redistributing lymphocytes to the peripheral tissues. The equality between the total (sum of unbound and otelixizumab bound) CD3/TCR and unbound CD3/TCR was observed indicating a small number of otelixizumab-(CD3/TCR) complexes at the T cell surface. The down-modulation of CD3/TCR was described by a direct inhibitory effect. The 50% change in unbound CD3/TCR was not dependent on the disease and was achieved for CD4+ and CD8+ cells at otelixizumab concentrations: IC50,FR,CD4 = 0.0164 µg/ml and IC50,FR,CD8 = 0.0191 µg/ml.
Conclusions: The integrated PK/PD model was proposed and successfully applied to understand otelixizumab pharmacokinetics and the array of PD responses in subjects with psoriasis and diabetes.