Department of Pharmacy, The First Hospital of Changsha, Changsha, Hunan, China.
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China.
PLoS One. 2023 Sep 11;18(9):e0288794. doi: 10.1371/journal.pone.0288794. eCollection 2023.
The aim of this study was to evaluate factors that impact on voriconazole (VRC) population pharmacokinetic (PPK) parameters and explore the optimal dosing regimen for different CYP2C19 genotypes in Chinese paediatric patients. PPK analysis was used to identify the factors contributing to the variability in VRC plasma trough concentrations. A total of 210 VRC trough concentrations from 91 paediatric patients were included in the study. The median VRC trough concentration was 1.23 mg/L (range, 0.02 to 8.58 mg/L). At the measurement of all the trough concentrations, the target range (1.0~5.5 mg/L) was achieved in 52.9% of the patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.9% and 6.2% of patients, respectively. VRC trough concentrations were adjusted for dose (Ctrough/D), with normal metabolizers (NMs) and intermediate metabolizers (IMs) having significantly lower levels than poor metabolizers (PMs) (PN-P < 0.001, PI-P = 0.039). A one-compartment model with first-order absorption and elimination was suitable to describe the VRC pharmacokinetic characteristics. The final model of VRC PPK analysis contained CYP2C19 phenotype as a significant covariate for clearance. Dose simulations suggested that a maintenance dose of 9 mg/kg orally or 8 mg/kg intravenously twice daily was appropriate for NMs to achieve the target concentration. A maintenance dose of 9 mg/kg orally or 5 mg/kg intravenously twice daily was appropriate for IMs. Meanwhile, PMs could use lower maintenance dose and an oral dose of 6 mg/kg twice daily or an intravenous dose of 5mg/kg twice daily was appropriate. To increase the probability of achieving the therapeutic range and improving efficacy, CYP2C19 phenotype can be used to predict VRC trough concentrations and guide dose adjustments in Chinese pediatric patients.
本研究旨在评估影响伏立康唑（VRC）群体药代动力学（PPK）参数的因素，并探索不同 CYP2C19 基因型中国儿科患者的最佳给药方案。通过 PPK 分析来确定影响 VRC 血药谷浓度变异性的因素。本研究共纳入 91 例儿科患者的 210 个 VRC 血药谷浓度。VRC 血药谷浓度的中位数为 1.23mg/L（范围：0.028.58mg/L）。在所有血药谷浓度的测量中，52.9%的患者达到了目标范围（1.05.5mg/L），40.9%的患者为治疗窗下浓度，6.2%的患者为治疗窗上浓度。VRC 血药谷浓度经剂量（Ctrough/D）校正后，正常代谢者（NMs）和中间代谢者（IMs）的水平明显低于弱代谢者（PMs）（PN-P<0.001，PI-P=0.039）。VRC 的 PPK 分析采用一室模型，以一级吸收和消除为特征。最终的 VRC PPK 分析模型包含 CYP2C19 表型作为清除率的显著协变量。VRC 的药代动力学特征分析结果显示，口服 9mg/kg 或静脉滴注 8mg/kg ，每日两次的维持剂量适合 NMs 以达到目标浓度。口服 9mg/kg 或静脉滴注 5mg/kg ，每日两次的维持剂量适合 IMs。同时，PMs 可以使用较低的维持剂量，每日两次口服 6mg/kg 或静脉滴注 5mg/kg 较为合适。为提高达到治疗窗的概率和提高疗效，可以使用 CYP2C19 表型预测 VRC 血药谷浓度并指导中国儿科患者的剂量调整。
