Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
J Antimicrob Chemother. 2013 Nov;68(11):2592-9. doi: 10.1093/jac/dkt229. Epub 2013 Jun 13.
Voriconazole exhibits non-linear pharmacokinetics in adults and is said to be mainly metabolized by CYP2C19 and CYP3A4 to voriconazole-N-oxide. The aim of this study was to obtain data on steady-state pharmacokinetics after dosing for at least 14 days in patients taking additional medication and in vivo data on metabolites other than voriconazole-N-oxide.
Thirty-one patients receiving voriconazole as regular therapeutic drug treatment during hospitalization participated in this prospective study. Pharmacokinetic profiles were obtained for the 12 h (dosing interval) after the first orally administered dose (400 mg) or (if possible and) after an orally administered maintenance dose (200 mg) following intake for at least 14 days (n = 14 after first dose; n = 23 after maintenance dose). Blood and urine samples were collected and the concentrations of voriconazole and three of its metabolites (the N-oxide, hydroxy-voriconazole and dihydroxy-voriconazole) were determined, as well as the CYP2C19 genotype of the patients. All other drugs taken by the participating patients were evaluated.
A high variability of exposure (AUC) after the first dose was slightly reduced during steady-state dosing for voriconazole (82% to 71%) and the N-oxide (86% to 56%), remained high for hydroxy-voriconazole (79%) and even increased for dihydroxy-voriconazole (97% to 127%). In 16 of the 22 steady-state patients, trough plasma concentrations were <2 μg/mL. N-oxide plasma concentrations during steady state stayed almost constant. Hydroxylations of voriconazole seem to be quantitatively more important in its metabolism than N-oxidation.
High variability in voriconazole exposure, as well as low steady-state trough plasma concentrations, suggest that the suggested steady-state dosage of 200 mg twice a day has to be increased to prevent disease progression. Therapeutic drug monitoring is probably necessary to optimize the voriconazole dose for individual patients.
伏立康唑在成人中表现出非线性药代动力学，据说是主要通过 CYP2C19 和 CYP3A4 代谢为伏立康唑-N-氧化物。本研究的目的是在至少 14 天内服用额外药物的患者中获得至少 14 天的稳态药代动力学数据，并获得伏立康唑-N-氧化物以外的其他代谢物的体内数据。
31 名在住院期间接受伏立康唑常规治疗药物治疗的患者参与了这项前瞻性研究。在至少 14 天的时间内，首次口服（400mg）后或口服维持剂量（200mg）后 12 小时（给药间隔）获得药代动力学曲线（首次剂量后 n=14；维持剂量后 n=23）。采集血样和尿样，测定伏立康唑和其三种代谢物（N-氧化物、羟基伏立康唑和二羟基伏立康唑）的浓度，并测定患者的 CYP2C19 基因型。评估参与患者服用的所有其他药物。
首次剂量后的暴露（AUC）变异性较高，伏立康唑（82%降至 71%）和 N-氧化物（86%降至 56%）在稳态给药期间略有降低，羟基伏立康唑（79%）仍较高，二羟基伏立康唑（97%至 127%）甚至增加。在 22 名稳态患者中的 16 名，谷浓度<2μg/ml。稳态期间 N-氧化物的血浆浓度几乎保持不变。伏立康唑的羟基化在其代谢中似乎比 N-氧化更重要。
伏立康唑暴露的变异性高，以及低稳态谷浓度，表明建议的 200mg 每天两次的稳态剂量必须增加，以防止疾病进展。治疗药物监测可能是优化个体患者伏立康唑剂量的必要手段。
