Department of Pharmacy, the First Hospital of Changsha, Changsha, Hunan, China.
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Eur J Clin Pharmacol. 2023 Sep;79(9):1271-1278. doi: 10.1007/s00228-023-03538-9. Epub 2023 Jul 17.
The objective of this study was to evaluate factors influencing voriconazole (VRC) plasma trough concentrations and provide research data for optimizing VRC dosing in Chinese paediatric patients.
Medical records of inpatients were reviewed retrospectively. Multivariate linear regression analysis was used to identify the factors contributing to the variability of VRC plasma trough concentrations.
A total of 250 VRC plasma trough concentrations from 131 paediatric patients were included in the analysis. The median VRC plasma trough concentration was 1.28 mg·L (range, 0.02 to 9.69 mg·L). The target range was achieved in 51.6% of patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.4% and 8.0% of paediatric patients, respectively. The most commonly identified cytochrome P450 2C19 (CYP2C19) phenotype was intermediate metabolizers (IMs) (48.9%), followed by normal metabolizers (NMs) (40.5%) and poor metabolizers (PMs) (10.7%), but no ultrarapid metabolizers (UMs) were observed in our study. VRC plasma trough concentrations adjusted for dose (C/D) were significantly lower in both NMs and IMs compared to PMs (P < 0.001 and P = 0.010, respectively). The dosage of VRC required to achieve the therapeutic range was related to age, with children aged < 6 years needing a significantly higher oral dose of VRC. The oral and intravenous maintenance doses needed to reach the therapeutic range were significantly lower than the recommended maintenance dose (P < 0.001, P < 0.001). Factors such as CYP2C19 polymorphisms, the combination of omeprazole, levels of albumin and alanine aminotransferase, were found to affect VRC exposure and explained some of the variability.
The VRC plasma trough concentration is significantly influenced by the CYP2C19 phenotype. The recommended maintenance dose for pediatric patients may not be appropriate for Chinese patients. To increase the probability of achieving the therapeutic range for VRC plasma trough concentration, the administration of VRC should consider the age of paediatric patients and the presence of CYP2C19 polymorphisms.
本研究旨在评估影响伏立康唑（VRC）血药谷浓度的因素，并为优化中国儿科患者的 VRC 剂量提供研究数据。
回顾性分析住院患者的病历。采用多元线性回归分析确定导致 VRC 血药谷浓度变异性的因素。
共纳入 131 例儿科患者的 250 个 VRC 血药谷浓度。VRC 血药谷浓度的中位数为 1.28 mg·L（范围：0.02 至 9.69 mg·L）。51.6%的患者达到目标范围，40.4%和 8.0%的患者分别获得亚治疗和超治疗浓度。最常见的细胞色素 P450 2C19（CYP2C19）表型为中间代谢型（IMs）（48.9%），其次为正常代谢型（NMs）（40.5%）和慢代谢型（PMs）（10.7%），但本研究中未观察到超快代谢型（UMs）。与 PMs 相比，NMs 和 IMs 的 VRC 血药谷浓度校正剂量（C/D）均显著降低（P<0.001 和 P=0.010）。达到治疗范围所需的 VRC 剂量与年龄有关，6 岁以下儿童需要显著更高的 VRC 口服剂量。达到治疗范围所需的口服和静脉维持剂量均显著低于推荐的维持剂量（P<0.001，P<0.001）。CYP2C19 多态性、奥美拉唑联合用药、白蛋白和丙氨酸氨基转移酶水平等因素均影响 VRC 暴露，并解释了部分变异性。
VRC 血药谷浓度受 CYP2C19 表型显著影响。推荐的儿科患者维持剂量可能不适用于中国患者。为提高 VRC 血药谷浓度达到治疗范围的概率，应考虑儿科患者的年龄和 CYP2C19 多态性，给予 VRC 治疗。
