异烟肼、利福平、吡嗪酰胺、乙胺丁醇四联药物抗结核治疗方案对初治涂阳肺结核患者肝功能的影响
Pharmacokinetic/Pharmacodynamic Analysis of Voriconazole Against Candida spp. and Aspergillus spp. in Allogeneic Stem Cell Transplant Recipients.
机构信息
Pharmacy Department, University Clinical Hospital of Valencia, Valencia, Spain.
Pharmacy Department, Doctor Peset University Hospital, Valencia, Spain.
出版信息
Ther Drug Monit. 2019 Dec;41(6):740-747. doi: 10.1097/FTD.0000000000000657.
BACKGROUND
To evaluate the adequacy of different dosing regimens of voriconazole for the prophylaxis of invasive candidiasis and aspergillosis in adult allogeneic stem cell transplant recipients by means of population pharmacokinetic (PK) modelling and simulation.
METHODS
Allogeneic stem cell transplant recipients receiving voriconazole were included in this observational study. A population PK model was developed. Three oral voriconazole-dosing regimens were simulated: 200, 300, and 400 mg twice daily. The pharmacodynamic target was defined as fAUC0-24/0.7. A probability of target attainment ≥90% was considered optimal. The cumulative fraction of response was defined as the fraction of patients achieving the pharmacodynamic target when a population of simulated patients is matched with a simulated population of different Candida spp. and Aspergillus spp. The percentage of patients with trough plasma concentrations at steady state (Ctrough) within the reference range (1-5.5 mg/L) was also calculated.
RESULTS
A 2-compartment PK model was developed using data from 40 patients, which contributed 237 voriconazole plasma samples, including trough and maximum concentrations. Voriconazole 200, 300, and 400 mg twice daily achieved probability of target attainment ≥90% for minimal inhibitory concentration values ≤0.25, ≤0.38, and ≤0.50 mg/L, respectively. The cumulative fraction of response for A. niger, A. versicolor, and A. flavus increased >10% when increasing voriconazole dose from 200 to 400 mg twice daily (from 72.5% to 89.5% for A. niger; from 77.7% to 88.7% for A. versicolor; and from 82.4% to 94.9% for A flavus). The percentage of patients with Ctrough within the reference range increased 15% when voriconazole dose was increased from 200 to 300 mg twice daily.
CONCLUSIONS
The PK simulations in this study suggest that transplant recipients on voriconazole prophylaxis against invasive candidiasis or aspergillosis are likely to achieve the target concentrations associated with the desired treatment outcomes if the maintenance dose is 200 mg twice daily. However, Aspergillus spp. with high minimal inhibitory concentrations could require higher maintenance doses.
背景
通过群体药代动力学（PK）建模和模拟来评估伏立康唑预防成人异基因造血干细胞移植受者侵袭性念珠菌病和曲霉病的不同剂量方案的适宜性。
方法
本观察性研究纳入了接受伏立康唑治疗的异基因造血干细胞移植受者。建立了群体 PK 模型。模拟了三种口服伏立康唑给药方案：200、300 和 400 mg 每日两次。药效学目标定义为 fAUC0-24/0.7。当模拟患者群体与不同念珠菌属和曲霉属的模拟群体相匹配时，达到目标的概率≥90%被认为是最佳的。累积反应率定义为当匹配模拟人群中不同的念珠菌属和曲霉属时，达到药效学目标的患者比例。还计算了在稳态时（Ctrough）的患者在参考范围内（1-5.5 mg/L）的浓度百分比。
结果
使用 40 名患者的 237 个伏立康唑血浆样本数据（包括谷值和最大值）建立了一个 2 隔室 PK 模型。伏立康唑 200、300 和 400 mg 每日两次给药方案，对最小抑菌浓度值≤0.25、≤0.38 和≤0.50 mg/L 的方案，达到目标的概率≥90%。当伏立康唑剂量从 200 mg 增加到 400 mg 每日两次时，黑曲霉、变色曲霉和黄曲霉的累积反应率增加了>10%（黑曲霉从 72.5%增加到 89.5%；变色曲霉从 77.7%增加到 88.7%；黄曲霉从 82.4%增加到 94.9%）。当伏立康唑剂量从 200 mg 增加到 300 mg 每日两次时，Ctrough 在参考范围内的患者百分比增加了 15%。
结论
本研究的 PK 模拟表明，接受伏立康唑预防侵袭性念珠菌病或曲霉病的移植受者，如果维持剂量为 200 mg 每日两次，可能会达到与所需治疗效果相关的目标浓度。然而，对于最小抑菌浓度较高的曲霉属，可能需要更高的维持剂量。
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