University of Pittsburgh, Medical Center, Pittsburgh, PA 15232, USA.
Antimicrob Agents Chemother. 2010 Feb;54(2):852-9. doi: 10.1128/AAC.00429-09. Epub 2009 Nov 23.
The objective of this study was to evaluate the pharmacokinetics of voriconazole and the potential correlations between pharmacokinetic parameters and patient variables in liver transplant patients on a fixed-dose prophylactic regimen. Multiple blood samples were collected within one dosing interval from 15 patients who were initiated on a prophylactic regimen of voriconazole at 200 mg enterally (tablets) twice daily starting immediately posttransplant. Voriconazole plasma concentrations were measured using high-pressure liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters. The mean apparent systemic clearance over bioavailability (CL/F), apparent steady-state volume of distribution over bioavailability (Vss/F), and half-life (t1/2) were 5.8+/-5.5 liters/h, 94.5+/-54.9 liters, and 15.7+/-7.0 h, respectively. There was a good correlation between the area under the concentration-time curve from 0 h to infinity (AUC0-infinity) and trough voriconazole plasma concentrations. t1/2, maximum drug concentration in plasma (Cmax), trough level, AUC0-infinity, area under the first moment of the concentration-time curve from 0 h to infinity (AUMC0-infinity), and mean residence time from 0 h to infinity (MRT0-infinity) were significantly correlated with postoperative time. t1/2, lambda, AUC0-infinity, and CL/F were significantly correlated with indices of liver function (aspartate transaminase [AST], total bilirubin, and international normalized ratio [INR]). The Cmax, last concentration in plasma at 12 h (Clast), AUMC0-infinity, and MRT0-infinity were significantly lower in the presence of deficient CYP2C19*2 alleles. Donor characteristics had no significant correlation with any of the pharmacokinetic parameters estimated. A fixed dosing regimen of voriconazole results in a highly variable exposure of voriconazole in liver transplant patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), the voriconazole dose can be individualized based on trough concentration measurements in liver transplant patients.
本研究的目的是评估伏立康唑在肝移植患者中的药代动力学，以及药代动力学参数与患者变量之间的潜在相关性。15 例患者在移植后立即开始每日两次（片剂）口服 200mg 伏立康唑的预防性方案，在一个给药间隔内采集了多个血样。使用高效液相色谱法（HPLC）测定伏立康唑的血浆浓度。采用非房室药代动力学分析方法估算药代动力学参数。生物利用度的表观全身清除率（CL/F）、生物利用度的表观稳态分布容积（Vss/F）和半衰期（t1/2）的平均值分别为 5.8+/-5.5 升/小时、94.5+/-54.9 升和 15.7+/-7.0 小时。AUC0-无穷大（AUC0-infinity）与伏立康唑的谷浓度之间存在良好的相关性。t1/2、最大血药浓度（Cmax）、谷浓度、AUC0-infinity、0 至无穷大的浓度-时间曲线下的第一矩面积（AUMC0-infinity）和 0 至无穷大的平均驻留时间（MRT0-infinity）与术后时间显著相关。t1/2、lambda、AUC0-infinity 和 CL/F 与肝功能指标（天冬氨酸转氨酶[AST]、总胆红素和国际标准化比值[INR]）显著相关。Cmax、12 小时末血浆浓度（Clast）、AUMC0-infinity 和 MRT0-infinity 在存在 CYP2C19*2 等位基因缺陷的情况下显著降低。供体特征与估计的任何药代动力学参数均无显著相关性。伏立康唑的固定剂量方案导致肝移植患者伏立康唑的暴露高度可变。鉴于伏立康唑的谷浓度是药物暴露（AUC）的良好衡量标准，因此可以根据肝移植患者的谷浓度测量结果对伏立康唑剂量进行个体化。
