Pharmacokinetics of murine anti-human CD3 antibodies in man are determined by the disappearance of target antigen.
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.
Meijer
R T
RT
Department of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
Koopmans
R P
RP
ten Berge
I J M
IJ
Schellekens
P T A
PT
D000465:Algorithms; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control; D006207:Half-Life; D006801:Humans; D016030:Kidney Transplantation / Q000502:physiology; D018655:Lymphocyte Count; D051379:Mice; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex