Vanstraelen Kim, Maertens Johan, Augustijns Patrick, Lagrou Katrien, de Loor Henriette, Mols Raf, Annaert Pieter, Malfroot Anne, Spriet Isabel
Clinical Pharmacology and Pharmacotherapy, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000, Leuven, Belgium.
Acute Leukaemia and Stem Cell Transplantation Unit, Clinical Department of Haematology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
Clin Pharmacokinet. 2015 Nov;54(11):1151-60. doi: 10.1007/s40262-015-0269-z.
Therapeutic drug monitoring (TDM) of voriconazole is increasingly being implemented in clinical practice. However, as blood sampling can be difficult in paediatric and ambulatory patients, a non-invasive technique for TDM is desirable. The aim of this study was to compare the pharmacokinetics of voriconazole in saliva with the pharmacokinetics of unbound and total voriconazole in plasma in order to clinically validate saliva as an alternative to plasma in voriconazole TDM.
In this pharmacokinetic study, paired plasma and saliva samples were taken at steady state in adult haematology and pneumology patients treated with voriconazole. Unbound and bound plasma voriconazole concentrations were separated using high-throughput equilibrium dialysis. Voriconazole concentrations were determined with liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using log-linear regression.
Sixty-three paired samples were obtained from ten patients (seven haematology and three pneumology patients). Pearson's correlation coefficients (R values) for saliva versus unbound and total plasma voriconazole concentrations showed a very strong correlation, with values of 0.970 (p < 0.001) and 0.891 (p < 0.001), respectively. Linear mixed modelling revealed strong agreement between voriconazole concentrations in saliva and unbound plasma voriconazole concentrations, with a mean bias of -0.03 (95 % confidence interval -0.14 to 0.09; p = 0.60). For total concentrations below 10 mg/L, the mean ratio of saliva to total plasma voriconazole concentrations was 0.51 ± 0.08 (n = 63), which did not differ significantly (p = 0.76) from the unbound fraction of voriconazole in plasma of 0.49 ± 0.03 (n = 36).
Saliva can serve as a reliable alternative to plasma in voriconazole TDM, and it can easily be implemented in clinical practice.
伏立康唑的治疗药物监测（TDM）在临床实践中的应用日益广泛。然而，由于儿科和门诊患者采血困难，一种非侵入性的TDM技术很有必要。本研究的目的是比较伏立康唑在唾液中的药代动力学与血浆中游离和总伏立康唑的药代动力学，以便在临床上验证唾液可作为伏立康唑TDM中血浆的替代物。
在这项药代动力学研究中，对接受伏立康唑治疗的成年血液科和呼吸科患者在稳态时采集配对的血浆和唾液样本。使用高通量平衡透析法分离血浆中游离和结合的伏立康唑浓度。采用液相色谱 - 串联质谱法测定伏立康唑浓度。使用对数线性回归计算药代动力学参数。
从10名患者（7名血液科患者和3名呼吸科患者）获得了63对样本。唾液与血浆中游离和总伏立康唑浓度的Pearson相关系数（R值）显示出很强的相关性，分别为0.970（p < 0.001）和0.891（p < 0.001）。线性混合模型显示唾液中伏立康唑浓度与血浆中游离伏立康唑浓度之间具有高度一致性，平均偏差为 -0.03（95%置信区间 -0.14至0.09；p = 0.60）。对于总浓度低于10mg/L的情况，唾液与血浆中总伏立康唑浓度的平均比值为0.51±0.08（n = 63），与血浆中伏立康唑游离分数0.49±0.03（n = 36）相比无显著差异（p = 0.76）。
在伏立康唑TDM中，唾液可作为血浆的可靠替代物，且能轻松应用于临床实践。
