Ling Jing, Yang Xuping, Dong Lulu, Jiang Yan, Zou Sulan, Hu Nan
Department of Pharmacy, The First People's Hospital of Changzhou/The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
Front Pharmacol. 2024 Aug 20;15:1455721. doi: 10.3389/fphar.2024.1455721. eCollection 2024.
Voriconazole is a broad-spectrum triazole antifungal agent. A number of studies have revealed that the impact of C-reactive protein (CRP) on voriconazole pharmacokinetics was associated with the phenotype. However, the combined effects of genetic polymorphisms and inflammation on voriconazole pharmacokinetics have not been considered in previous population pharmacokinetic (PPK) studies, especially in the Chinese population. This study aimed to analyze the impact of inflammation on the pharmacokinetics of voriconazole in patients with different genotypes and optimize the dosage of administration. Data were obtained retrospectively from adult patients aged ≥16 years who received voriconazole for invasive fungal infections from October 2020 to June 2023. Plasma voriconazole levels were measured via high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). genotyping was performed using the fluorescence hybridization method. A PPK model was developed using the nonlinear mixed-effect model (NONMEM). The final model was validated using bootstrap, visual predictive check (VPC), and normalized prediction distribution error (NPDE). The Monte Carlo simulation was applied to evaluate and optimize the dosing regimens. A total of 232 voriconazole steady-state trough concentrations from 167 patients were included. A one-compartment model with first order and elimination adequately described the data. The typical clearance (CL) and the volume of distribution (V) of voriconazole were 3.83 L/h and 134 L, respectively. The bioavailability was 96.5%. Covariate analysis indicated that the CL of voriconazole was substantially influenced by age, albumin, gender, CRP, and genetic variations. The V of voriconazole was significantly associated with body weight. An increase in the CRP concentration significantly decreased voriconazole CL in patients with the CYP2C19 normal metabolizer (NM) and intermediate metabolizer (IM), but it had no significant effect on patients with the CYP2C19 poor metabolizer (PM). The Monte Carlo simulation based on CRP levels indicated that patients with high CRP concentrations required a decreased dose to attain the therapeutic trough concentration and avoid adverse drug reactions in NM and IM patients. These results indicate that CRP affects the pharmacokinetics of voriconazole and is associated with the CYP2C19 phenotype. Clinicians dosing voriconazole should consider the patient's CRP level, especially in CYP2C19 NMs and IMs.
伏立康唑是一种广谱三唑类抗真菌药物。多项研究表明，C反应蛋白（CRP）对伏立康唑药代动力学的影响与表型有关。然而，以往的群体药代动力学（PPK）研究，尤其是在中国人群中，尚未考虑基因多态性和炎症对伏立康唑药代动力学的联合影响。本研究旨在分析炎症对不同基因型患者伏立康唑药代动力学的影响，并优化给药剂量。数据回顾性收集自2020年10月至2023年6月因侵袭性真菌感染接受伏立康唑治疗的≥16岁成年患者。通过高效液相色谱-串联质谱法（HPLC-MS/MS）测定血浆伏立康唑水平。采用荧光杂交法进行基因分型。使用非线性混合效应模型（NONMEM）建立PPK模型。最终模型通过自抽样法、可视化预测检查（VPC）和标准化预测分布误差（NPDE）进行验证。应用蒙特卡洛模拟评估和优化给药方案。共纳入167例患者的232个伏立康唑稳态谷浓度。一个具有一级消除的单室模型充分描述了数据。伏立康唑的典型清除率（CL）和分布容积（V）分别为3.83 L/h和134 L。生物利用度为96.5%。协变量分析表明，伏立康唑的CL受年龄、白蛋白、性别、CRP和基因变异的显著影响。伏立康唑的V与体重显著相关。CRP浓度升高显著降低CYP2C19正常代谢者（NM）和中间代谢者（IM）患者的伏立康唑CL，但对CYP2C19慢代谢者（PM）患者无显著影响。基于CRP水平的蒙特卡洛模拟表明，高CRP浓度的患者需要降低剂量以达到治疗谷浓度，并避免NM和IM患者出现药物不良反应。这些结果表明，CRP影响伏立康唑的药代动力学，并与CYP2C19表型相关。临床医生在给患者使用伏立康唑时应考虑患者的CRP水平，尤其是在CYP2C19 NM和IM患者中。
