College of Pharmacy, University of Iowa, Iowa City, IA, USA.
Malar J. 2009 Dec 18;8:304. doi: 10.1186/1475-2875-8-304.
The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food.
Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates.
A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9-unit change in CLM/F in the same direction.
A novel simultaneous parent-metabolite pharmacokinetic model with good predictive power was developed to study the population pharmacokinetics of AS and DHA in healthy subjects following single- and multiple-dosing of AS with or without the presence of food. Food intake and weight were significant covariates for Ka and CLM/F, respectively.
本研究旨在评估健康受试者单剂量和多剂量口服青蒿琥酯（AS）及其活性代谢物双氢青蒿素（DHA）时，合并或不合并吡喹酮（PYR）用药以及与或不与食物同服时的群体药代动力学特征。
共纳入 91 例健康韩国受试者，分别参与了 4 项 I 期临床试验，共采集了 118 个血药浓度-时间数据。受试者以 2-5mg/kg 剂量单剂量和多剂量口服 AS，合并或不合并 PYR 用药，与或不与食物同服。采用液质联用方法检测血浆中 AS 和 DHA 浓度，检测下限为 1ng/ml。采用非线性混合效应模型分析获得药代动力学和变异性（个体间和残差变异性）参数。
本研究建立了一个包含给药室、AS 中央室、DHA 中央室和外周室的新型母体-代谢物药代动力学模型。该模型假设 AS 转化为 DHA 呈化学计量关系。AS 吸收迅速，群体吸收速率常数（Ka）的估算值为 3.85h-1。AS 的群体表观清除率（CL/F）和中央分布容积（V2/F）的估算值分别为 1190L/h 和 36.2%个体间变异性（IIV）、1210L 和 57.4%IIV。DHA 的群体表观清除率（CLM/F）和中央分布容积（V3/F）的估算值分别为 93.7L/h 和 28%IIV、97.1L 和 30%IIV。DHA 的群体估算表观跨室清除率（Q/F）和外周分布容积（V4/F）分别为 5.74L/h 和 18.5L。用药前摄入高脂肪、高热量食物会导致 Ka 降低 84%。体重会影响 CLM/F，体重每增加 1 个单位，CLM/F 也会同向增加 1.9 个单位。
本研究建立了一个具有良好预测能力的新型母体-代谢物群体药代动力学模型，用于研究健康受试者单剂量和多剂量口服 AS 时，以及是否与食物同服时 AS 和 DHA 的群体药代动力学特征。进食和体重分别是 Ka 和 CLM/F 的显著协变量。
