Abstract
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.
Abbreviations
- mAbs
- monoclonal antibodies
- ELISA
- enzyme-linked immunosorbent assay
- HAMAs
- human anti-mouse antibodies
- PBMC
- mononuclear cells from peripheral blood
- TCR
- T cell receptor
- FACS
- fluorescence-activated cell sorter
- FITC
- fluorescein isothiocyanate
- MFI
- mean fluorescence intensities
- PBS
- phosphate-buffered saline
- Received March 2, 2001.
- Accepted August 2, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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