Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
Br J Clin Pharmacol. 2021 Apr;87(4):1890-1902. doi: 10.1111/bcp.14578. Epub 2020 Nov 5.
Voriconazole is a broad-spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (C ) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction.
The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic curves were used to explore the relationship between voriconazole C and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by total bilirubin (TBIL, TBIL-1: TBIL < 51 μmol/L; TBIL-2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL-3: TBIL ≥ 171 μmol/L) were performed.
Receiver operating characteristic curve analysis revealed that voriconazole C of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A 1-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance, volume of distribution and oral bioavailability were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole clearance was significantly associated with TBIL and platelet count. The volume of distribution increased with body weight. Patients with TBIL-1 could be treated with a loading dose of 400 mg every 12 hours (q12h) for first day, followed by a maintenance dose of 100 mg q12h administered orally or intravenously. TBIL-2 and TBIL-3 patients could be treated with a loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily and 50 mg once daily orally or intravenously, respectively.
Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL-based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.
伏立康唑是一种广谱抗真菌药物，用于治疗侵袭性真菌感染。目前关于肝功能不全患者伏立康唑的药代动力学和合适剂量的信息有限。本研究旨在探讨伏立康唑谷浓度（C）与毒性之间的关系，确定与伏立康唑药代动力学参数显著相关的因素，并为肝功能不全患者提出优化的伏立康唑给药方案。
本研究前瞻性纳入 51 例患者，共 272 个伏立康唑浓度。采用受试者工作特征曲线（ROC 曲线）探讨伏立康唑 C 与毒性之间的关系。采用非线性混合效应模型分析药代动力学数据。根据总胆红素（TBIL）进行分层给药模拟（TBIL-1：TBIL＜51 μmol/L；TBIL-2：51 μmol/L≤TBIL＜171 μmol/L；TBIL-3：TBIL≥171 μmol/L）。
ROC 曲线分析显示，伏立康唑 C 值≤5.1mg/L 与不良反应发生率显著降低相关。采用一室模型加吸收和消除的一级动力学过程描述数据。清除率、分布容积和口服生物利用度的群体药代动力学参数分别为 0.88 L/h、148.8 L 和 88.4%。伏立康唑清除率与 TBIL 和血小板计数显著相关。分布容积随体重增加而增加。TBIL-1 患者第 1 天可给予负荷剂量 400mg，q12h，随后给予维持剂量 100mg，q12h，口服或静脉给药。TBIL-2 和 TBIL-3 患者可给予负荷剂量 200mg，q12h，维持剂量 50mg，q12h，或 100mg，qd，口服或静脉给药；50mg，qd，口服或静脉给药。
肝功能不全患者应考虑降低剂量和延长给药间隔。基于 TBIL 的给药方案为实现伏立康唑治疗窗和最大治疗效果提供了一种实用策略。
