Pharmacokinetics/pharmacodynamics of nondepleting anti-CD4 monoclonal antibody (TRX1) in healthy human volunteers.
OBJECTIVE
TRX1 is a nondepleting anti-CD4 monoclonal IgG1 antibody being developed to induce tolerance by blocking CD4-mediated functions. The purpose of this study is to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of TRX1 and to develop a receptor-mediated PK/PD model that characterizes the relationships between serum TRX1 concentration and total and free CD4 expression in healthy male volunteers.


METHODS
Nine subjects from three dosing cohorts in double-blinded, placebo-controlled phase I clinical study was included in the analysis. Serum TRX1 levels were determined using enzyme-linked immunosorbent assay. Blood total and free CD4 receptor levels were determined by using flow cytometric analyses. The receptor-mediated PK/PD model was developed to describe the dynamic interaction of TRX1 binding with CD4 receptors.


CONCLUSIONS
TRX1 displayed nonlinear pharmacokinetic behavior and the CD4 receptors on T cells were saturated and down-modulated following treatment with TRX1. Results from in vitro studies using purified human T cells suggested that CD4-mediated internalization may constitute one pathway by which CD4 is down-modulated and TRX1 is cleared in vivo. The developed receptor-mediated PK/PD model adequately described the data. This PK/PD model was used to simulate PK/PD time profiles after different dosing regimens to help guide the dose selection in future clinical studies.
Ng
Chee M
CM
Department of Pharmacokinetic and Pharmacodynamic Sciences, MS 70, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA. Ng.chee@gene.com
Stefanich
Eric
E
Anand
Banmeet S
BS
Fielder
Paul J
PJ
Vaickus
Louis
L
D000465:Algorithms; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D008565:Membrane Proteins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D054464:Peroxiredoxins; D016032:Randomized Controlled Trials as Topic; D029701:Saccharomyces cerevisiae Proteins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013879:Thioredoxins / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; C103243:TRX1 protein, S cerevisiae; D013879:Thioredoxins; D054464:Peroxiredoxins