Pharmacokinetics/pharmacodynamics of nondepleting anti-CD4 monoclonal antibody (TRX1) in healthy human volunteers.
Pharm Res
; 23(1): 95-103, 2006 Jan.
Article
en En
| MEDLINE
| ID: mdl-16308668
ABSTRACT
PURPOSE:
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. RESULTS ANDCONCLUSIONS:
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.
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Banco de datos:
MEDLINE
Asunto principal:
Tiorredoxinas
/
Antígenos CD4
/
Proteínas de Saccharomyces cerevisiae
/
Proteínas de la Membrana
/
Anticuerpos Monoclonales
Tipo de estudio:
Clinical_trials
Límite:
Humans
Idioma:
En
Revista:
Pharm Res
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos