Pharmacokinetics/Pharmacodynamics of Nondepleting Anti-CD4 Monoclonal Antibody (TRX1) in Healthy Human Volunteers

Abstract

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.

A mathematical analysis of rebound in a target-mediated drug disposition model: I.Without feedback

“…Binding to cell-surface receptors typically results in accelerated turnover of the antibody and the complex (e.g. Ng et al (2006) ;Wang et al (2012)). There are no reports known to the authors where binding to cell-surface receptor leads to formation of complexes that are cleared slower than the receptor or ligand.…”

Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys

“…27 In contrast, the clearance of antibodies targeting cell-surface antigens can be greatly accelerated through a target-mediated process and result in dose-dependent nonlinear kinetics. 28 In the case of the anti-CD81 antibody K21, we observed steep nonlinear PK ( Fig. 2 and Table 1).…”

Pharmacocinétique des anticorps monoclonaux

“…Il a par ailleurs été montré que le nombre de sites métastati-ques influence la PK du trastuzumab chez les patientes traitées [35]. Pour décrire l'interdépendance entre la PK et la pharmacodynamie, des modèles pharmacocinétiques-pharmacodynamiques (PK-PD) spécifiques doivent être développés [37,38]. [32].…”