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Abstract：
Precision dosing for many antifungal drugs is now recommended. Saliva sampling is considered as a non-invasive alternative to plasma sampling for therapeutic drug monitoring (TDM). However, there are currently no clinically validated saliva models available. The aim of this study is firstly, to conduct a systematic review to evaluate the evidence supporting saliva-based TDM for azoles, echinocandins, amphotericin B, and flucytosine. The second aim is to develop a saliva population pharmacokinetic (PK) model for eligible drugs, based on the evidence. Databases were searched up to July 2019 on PubMed® and Embase®, and 14 studies were included in the systematic review for fluconazole, voriconazole, itraconazole, and ketoconazole. No studies were identified for isavuconazole, posaconazole, flucytosine, amphotericin B, caspofungin, micafungin, or anidulafungin. Fluconazole and voriconazole demonstrated a good saliva penetration with an average S/P ratio of 1.21 (± 0.31) for fluconazole and 0.56 (± 0.18) for voriconazole, both with strong correlation (r = 0.89-0.98). Based on the evidence for TDM and available data, population PK analysis was performed on voriconazole using Nonlinear Mixed Effects Modeling (NONMEM 7.4). 137 voriconazole plasma and saliva concentrations from 11 patients (10 adults, 1 child) were obtained from the authors of the included study. Voriconazole pharmacokinetics was best described by one-compartment PK model with first-order absorption, parameterized by clearance of 4.56 L/h (36.9% CV), volume of distribution of 60.7 L, absorption rate constant of 0.858 (fixed), and bioavailability of 0.849. Kinetics of the voriconazole distribution from plasma to saliva was identical to the plasma kinetics, but the extent of distribution was lower, modeled by a scale factor of 0.5 (4% CV). A proportional error model best accounted for the residual variability. The visual and simulation-based model diagnostics confirmed a good predictive performance of the saliva model. The developed saliva model provides a promising framework to facilitate saliva-based precision dosing of voriconazole.
摘要：
现在建议对许多抗真菌药物进行精确给药。唾液采样被认为是用于治疗药物监测（TDM）的血浆采样的非侵入性替代方法。然而,目前尚无临床验证的唾液模型.本研究的目的首先是,进行系统评价以评估支持基于唾液的唑类TDM的证据，棘白菌素,两性霉素B,和氟胞嘧啶.第二个目标是为符合条件的药物开发唾液群体药代动力学（PK）模型，基于证据。截至2019年7月，在PubMed®和Embase®上搜索了数据库，14项研究纳入了氟康唑的系统评价，伏立康唑,伊曲康唑,和酮康唑.没有发现伊沙武康唑的研究，泊沙康唑,氟胞嘧啶,两性霉素B,卡波芬金,米卡芬净,或者Anidulafungin.氟康唑和伏立康唑表现出良好的唾液渗透，氟康唑的平均S/P比为1.21（±0.31），伏立康唑为0.56（±0.18）。两者具有很强的相关性(r=0.89-0.98)。根据TDM的证据和现有数据，采用非线性混合效应模型(NONMEM7.4)对伏立康唑进行群体PK分析。来自11名患者的137种伏立康唑血浆和唾液浓度（10名成人，1名儿童）是从纳入研究的作者那里获得的。伏立康唑药代动力学最好用一级吸收的一室PK模型来描述，通过4.56L/h（36.9%CV）的间隙参数化，60.7L的分布体积，吸收率常数0.858（固定），生物利用度为0.849。伏立康唑从血浆到唾液的分布动力学与血浆动力学相同，但是分布程度较低，由0.5的比例因子(4%CV)建模。比例误差模型最好地解释了残差变异性。视觉和基于模拟的模型诊断证实了唾液模型的良好预测性能。开发的唾液模型提供了一个有希望的框架，以促进伏立康唑的基于唾液的精确给药。
