Mager Donald E, Jusko William J
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 14260, USA.
Pharm Res. 2002 Oct;19(10):1537-43. doi: 10.1023/a:1020468902694.
An integrated receptor-based pharmacokinetic/pharmacodynamic (PK/PD) model of interferon-beta la (IFN-beta la) previously developed for monkeys was used to capture the time-course of drug and induced neopterin concentrations after intravenous (IV) and subcutaneous (SC) dosing in humans.
Data were extracted from the literature by digitalization. Single-dose (3 IV doses and I SC dose) PK/PD profiles were simultaneously fitted using the basic model and the ADAPT II computer program. Additional submodels incorporating neutralizing antibody formation and negative feedback inhibition were applied to account for drug accumulation and lower than expected neopterin concentrations encountered after multiple-dosing (1 SC dose every 48 hs).
The basic model jointly-captured the nonlinear PK behavior of the drug and induced neopterin concentrations after all single doses. Slow and incomplete absorption (F = 0.33) of the SC dose resulted in prolonged drug concentrations reflective of flip-flop kinetics. Despite lower drug concentrations, SC dosing produced a similar neopterin profile as compared with the IV doses; however, with a longer time to peak effect and slightly higher neopterin concentrations at later time points. The PD component of the model represents a modified precursor-dependent indirect response model driven by the amount of internalized drug-receptor complex. The latter stimulated a 6-fold increase in the production of the neopterin precursor (Smax = 5.89). Drug accumulation and lower than expected neopterin concentrations after multiple dosing were also captured after the inclusion of the submodels.
The present integrated PK/PD model for IFN-beta 1a is mechanistic in nature with receptor-mediated disposition and dynamics and was successfully applied to human clinical data.
先前为猴子建立的基于受体的干扰素-β1a（IFN-β1a）药代动力学/药效学（PK/PD）整合模型，用于描述人体静脉注射（IV）和皮下注射（SC）给药后药物及诱导的新蝶呤浓度的时间进程。
通过数字化从文献中提取数据。使用基本模型和ADAPT II计算机程序同时拟合单剂量（3次静脉注射剂量和1次皮下注射剂量）的PK/PD曲线。应用包含中和抗体形成和负反馈抑制的额外子模型，以解释多次给药（每48小时1次皮下注射剂量）后出现的药物蓄积以及低于预期的新蝶呤浓度。
基本模型共同描述了所有单剂量给药后药物的非线性PK行为以及诱导的新蝶呤浓度。皮下注射剂量吸收缓慢且不完全（F = 0.33），导致药物浓度延长，反映出翻转动力学。尽管药物浓度较低，但皮下注射给药与静脉注射剂量相比产生了相似的新蝶呤曲线；然而，达到峰值效应的时间更长，且在后期时间点新蝶呤浓度略高。该模型的PD部分代表了一种由内化的药物-受体复合物量驱动的改良前体依赖性间接反应模型。后者刺激新蝶呤前体的产生增加了6倍（Smax = 5.89）。纳入子模型后，也捕捉到了多次给药后的药物蓄积和低于预期的新蝶呤浓度。
目前的IFN-β1a PK/PD整合模型本质上是基于受体介导的处置和动力学的机制性模型，并成功应用于人体临床数据。
