Florent Aurélie, Gandia Peggy, Seraissol Patrick, Chatelut Etienne, Houin Georges
*Laboratory of Pharmacokinetics and Clinical Toxicology, Institute of Biology, University Hospital of Toulouse; and †EA4553 Laboratory of Pharmacokinetics, Claudius-Regaud Institute, Toulouse, France.
Ther Drug Monit. 2014 Dec;36(6):752-8. doi: 10.1097/FTD.0000000000000095.
Voriconazole (VOR) is a triazole antifungal used in the curative treatment of invasive fungal infections and the prophylactic treatment of opportunistic fungal infections in immunocompromised patients. It is a drug for which therapeutic drug monitoring (TDM) is highly recommended.
To determine the best TDM marker, the pharmacologically active form of the drug, represented by the plasma unbound concentration (Cu) and fraction (fu), has been studied using a method based on ultrafiltration and ultra performance liquid chromatography. As albumin (Alb) is a likely factor inducing fluctuations in fu, the correlation between Alb levels and fu was carried out. Similarly, correlations between trough plasma concentrations [total concentration (Ct) and Cu] and both efficacy and safety markers were determined. Efficacy evaluation was based on monitoring fungal antigens and cultures, whereas safety was monitored by measuring bilirubin levels.
In vitro, using blank human plasma, the mean fu was determined at 32.3% ± 5.5%, whereas in patients' plasmas treated with VOR, the median (5th-95th percentiles) of the unbound VOR fraction was 22.95% (14.95%-38.42%). A high correlation was found (rho = 0.956, P < 0.001) between Ct and Cu, though there was no correlation between serum Alb levels and fu, except for some patients with severe hypoalbuminemia (<25 g/L).
Based on the efficacy/safety correlations, a therapeutic window has been defined ranging from 4.5 to 6.5 mg/L and 1.5 and 2.0 mg/L for trough Ct and Cu, respectively. For the first time, the relevance of new pharmacokinetic parameters, such as Cu and fu, has been explored and discussed, and our results support the current TDM protocol for VOR.
伏立康唑（VOR）是一种三唑类抗真菌药物，用于侵袭性真菌感染的根治性治疗以及免疫功能低下患者机会性真菌感染的预防性治疗。这是一种强烈推荐进行治疗药物监测（TDM）的药物。
为了确定最佳的TDM标志物，采用基于超滤和超高效液相色谱的方法，研究了以血浆未结合浓度（Cu）和分数（fu）表示的药物药理活性形式。由于白蛋白（Alb）可能是导致fu波动的因素，因此进行了Alb水平与fu之间的相关性研究。同样，还确定了谷浓度[总浓度（Ct）和Cu]与疗效和安全性标志物之间的相关性。疗效评估基于监测真菌抗原和培养物，而安全性则通过测量胆红素水平进行监测。
在体外，使用空白人血浆，平均fu测定为32.3%±5.5%，而在用VOR治疗的患者血浆中，未结合VOR分数的中位数（第5-95百分位数）为22.95%（14.95%-38.42%）。Ct与Cu之间存在高度相关性（rho = 0.956，P < 0.001），尽管血清Alb水平与fu之间无相关性，但一些严重低白蛋白血症（<25 g/L）患者除外。
基于疗效/安全性相关性，已确定治疗窗，谷浓度Ct和Cu分别为4.5至6.5 mg/L和1.5至2.0 mg/L。首次探索并讨论了新的药代动力学参数（如Cu和fu）的相关性，我们的结果支持当前VOR的TDM方案。
