Meijer R T, Koopmans R P, ten Berge I J M, Schellekens P T A
Department of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
J Pharmacol Exp Ther. 2002 Jan;300(1):346-53. doi: 10.1124/jpet.300.1.346.
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.
单克隆抗体（mAb）治疗的特点是受体与药物的摩尔比高于药物治疗中的通常水平。因此，治疗诱导的受体数量变化可能对药代动力学产生重要影响。我们因此分析了一种实验性治疗性CD3抗体CLB-T3/4.A（鼠IgA）的药代动力学和药效学，该抗体用于肾移植患者的排斥反应治疗。患者每天静脉推注5 mg该单克隆抗体，持续10天。单克隆抗体的平均谷浓度在第1周升高，此后下降。然而，约三分之一的患者谷浓度持续升高，约三分之一呈现稳态，且仅在4天后才达到。治疗第一天，单克隆抗体浓度呈现双相血浆消除曲线。在随后的日子里，观察到单相血浆消除曲线，平均半衰期为6至8小时。单克隆抗体的给药导致外周血中靶抗原消失，这可以解释基于靶抗原耗竭的血浆浓度多剂量曲线模拟所显示的第1天和随后几天动力学的差异。我们得出结论，在此剂量下，CLB-T3/4.A的药代动力学在很大程度上由抗体诱导的外周血抗原变化所决定。此外，基于单剂量数据和传统房室模型的药代动力学和药效学参数测定对于预测和外推目的而言是不够的。
