Department of Drug Metabolism and Pharmacokinetics, Hoffmann-La Roche Inc, Nutley, New Jersey 07110, USA.
J Pharm Sci. 2012 Jan;101(1):414-23. doi: 10.1002/jps.22764. Epub 2011 Sep 20.
The elimination kinetics of the pharmacologically active compound 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline (MC4) were characterized along with pharmacodynamic (PD) measurements. Four compartmental models based on ocular anatomy, physiology, and possible absorption and disposition pathways were proposed to model the pharmacokinetic (PK) data in WinNonlin and the best model was chosen based on statistical and goodness-of-fit criteria. A three-compartment physiologic-based PK model with a bidirectional transfer between cornea and aqueous humor and a unidirectional transfer between aqueous humor and iris-ciliary body best described the data. The ocular PD parameters, maximum effect attributed to drug (E(max)) and drug concentration which produces 50% of maximum effect (EC(50)), were estimated with change in intraocular pressure (ΔIOP) as the effect (PD response) in the effect compartment model (PK-PD link model) using aqueous humor concentration-time and ΔIOP-time profiles. The link model better described the effect compartment concentrations than a simple E(max) model that used iris-ciliary body concentration-time data, indicating that there is an apparent temporal displacement between aqueous humor concentration (plasma/central compartment equivalent) and pharmacological effect. A physiologically plausible value of 0.0159 min(-1) was obtained for the drug elimination rate constant (k(eo)) from the effect site to account for equilibration time in the biophase. Hysteresis was observed for the iris-ciliary body, aqueous humor drug concentrations, and effect data, further confirming the utility of the link model to describe the PD of MC4.
本文对具有药理活性的 1-乙基-6-氟-1,2,3,4-四氢喹啉（MC4）的消除动力学进行了特征描述，并进行了药效学（PD）测量。基于眼部解剖学、生理学以及可能的吸收和处置途径，提出了四个房室模型来对 WinNonlin 中的药代动力学（PK）数据进行建模，并根据统计和拟合优度标准选择了最佳模型。一个具有双向角膜-房水转运和单向房水-虹膜睫状体转运的三室生理基础 PK 模型能够最好地描述数据。眼部 PD 参数，即最大药效（E(max))和产生最大药效 50%的药物浓度（EC(50))，通过将眼压变化（ΔIOP）作为效应（PD 效应）来进行估计，效应室模型（PK-PD 链接模型）使用房水浓度-时间和 ΔIOP-时间曲线。链接模型比使用虹膜睫状体浓度-时间数据的简单 E(max)模型更好地描述了效应室浓度，表明房水浓度（血浆/中央室等效物）和药效之间存在明显的时间位移。从效应部位到消除率常数（k(eo))的药物消除速率常数（k(eo))的生理上合理的值为 0.0159 min(-1)，用于解释生物相中的平衡时间。对于虹膜睫状体、房水药物浓度和效应数据，观察到滞后现象，进一步证实了链接模型对 MC4 的 PD 描述的实用性。
