Vol. 300, Issue 1, 346-353, January 2002

Pharmacokinetics of Murine Anti-Human CD3 Antibodies in Man Are Determined by the Disappearance of Target Antigen

R. T. Meijer, R. P. Koopmans, I. J. M. ten Berge and P. T. A. Schellekens

Department of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands

Therapy with monoclonal antibodies (mAbs) is characterized by a molar ratio of receptor to drug that is higher than usual in pharmacotherapy. As a consequence, changes in the amount of receptors induced by the therapy may have important consequences for pharmacokinetics. We therefore analyzed the pharmacokinetics and pharmacodynamics of an experimental therapeutic CD3 antibody, CLB-T3/4.A (murine IgA), which was given as a rejection treatment to renal transplant patients. Patients were treated with 5 mg of the mAb, as a daily bolus injection, during 10 days. Mean trough levels of mAbs increased during the 1st week, and decreased thereafter. However, about one-third of the patients had continuously rising trough levels and about one-third displayed a steady state, that was reached only after 4 days. On the first day of treatment, mAb concentrations showed a biphasic plasma disappearance curve. On subsequent days, monophasic plasma disappearance curves were observed with mean half-lives of 6 to 8 h. Administration of the mAb induced disappearance of target antigen from the peripheral blood, which could explain the difference in kinetics between day 1 and subsequent days shown by a simulation of the multidose curve of plasma concentrations, based on target antigen depletion. We conclude that at this dose the pharmacokinetics of CLB-T3/4.A were to a great extent determined by antibody-induced changes in antigen in peripheral blood. Moreover, determinations of pharmacokinetic and pharmacodynamic parameters based on single-dose data and traditional compartment models were inadequate for the purpose of prediction and extrapolation.