The University of Manchester, Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
Antimicrob Agents Chemother. 2012 Jan;56(1):526-31. doi: 10.1128/AAC.00702-11. Epub 2011 Nov 7.
Voriconazole is a first-line agent for the treatment of invasive fungal infections. The pharmacology of voriconazole is characterized by extensive interindividual variability and nonlinear pharmacokinetics. The population pharmacokinetics of voriconazole in 64 adults is described. The patient population consisted of 21 healthy volunteers, who received a range of intravenous (i.v.) and oral voriconazole regimens, and 43 patients with proven or probable invasive aspergillosis, who received the currently licensed dosage. Voriconazole concentrations were measured using high-performance liquid chromatography (HPLC). The pharmacokinetic data were modeled using a nonparametric methodology and with a nonlinear pharmacokinetic structural model. The extent and consequences of pharmacokinetic variability were explored using Monte Carlo simulation. The relationship between drug exposure and clinical response was explored using logistic regression. Optimal sampling times were identified using D-optimal design. The fit of the nonlinear model was acceptable. Data from the healthy volunteers provided robust estimates for K(m) and the maximum rate of enzyme activity (V(max)). The Bayesian parameter estimates were more variable and statistically different in patients than in volunteers. There was a linear relationship between the trough concentration and area under the concentration-time curve (AUC(0-12)). There was no relationship between the AUC(0-12) and clinical response. The original parameter values were readily recapitulated using Monte Carlo simulation. Initial i.v. dosing resulted in higher AUC(0-12) and trough concentrations compared with oral dosing. Sample collection times of 1, 2, 3, 4, 8, and 12 h after an i.v. infusion are maximally informative times for future pharmacokinetic studies.
伏立康唑是治疗侵袭性真菌感染的一线药物。伏立康唑的药理学特征为广泛的个体间变异性和非线性药代动力学。本文描述了 64 例成年人伏立康唑的群体药代动力学。患者人群包括 21 名接受了不同静脉（i.v.）和口服伏立康唑方案的健康志愿者，以及 43 名确诊或疑似侵袭性曲霉菌病患者，他们接受了目前许可的剂量。使用高效液相色谱法（HPLC）测量伏立康唑浓度。使用非参数方法和非线性药代动力学结构模型对药代动力学数据进行建模。使用蒙特卡罗模拟探索药代动力学变异性的程度和后果。使用逻辑回归探索药物暴露与临床反应之间的关系。使用 D 最优设计确定最佳采样时间。非线性模型的拟合情况可接受。志愿者的数据为 K(m) 和最大酶活性速率（V(max)）提供了可靠的估计值。患者的贝叶斯参数估计值比志愿者更具变异性且统计学上不同。谷浓度与浓度-时间曲线下面积（AUC(0-12)）之间存在线性关系。AUC(0-12)与临床反应之间没有关系。使用蒙特卡罗模拟可以轻松再现原始参数值。与口服给药相比，初始静脉给药导致 AUC(0-12)和谷浓度更高。静脉输注后 1、2、3、4、8 和 12 小时采集样本是未来药代动力学研究的最佳信息采集时间。
