Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Drugs R D. 2021 Dec;21(4):419-429. doi: 10.1007/s40268-021-00365-0. Epub 2021 Oct 15.
The aim of this study was to identify factors affecting blood concentrations of voriconazole following letermovir coadministration using population pharmacokinetic (PPK) analysis in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients.
The following data were retrospectively collected: voriconazole trough levels, patient characteristics, concomitant drugs, and laboratory information. PPK analysis was performed with NONMEM version 7.4.3, using the first-order conditional estimation method with interaction. We collected data on plasma voriconazole steady-state trough concentrations at 216 timepoints for 47 patients. A nonlinear pharmacokinetic model with the Michaelis-Menten equation was applied to describe the relationship between steady-state trough concentration and daily maintenance dose of voriconazole. After stepwise covariate modeling, the final model was evaluated using a goodness-of-fit plot, case deletion diagnostics, and bootstrap methods.
The maximum elimination rate (V) of voriconazole in patients coadministered letermovir and methylprednisolone was 1.72 and 1.30 times larger than that in patients not coadministered these drugs, respectively, resulting in decreased voriconazole trough concentrations. The developed PPK model adequately described the voriconazole trough concentration profiles in allo-HSCT recipients. Simulations clearly showed that increased daily doses of voriconazole were required to achieve an optimal trough voriconazole concentration (1-5 mg/L) when patients received voriconazole with letermovir and/or methylprednisolone.
The development of individualized dose adjustment is critical to achieve optimal voriconazole concentration, especially among allo-HSCT recipients receiving concomitant letermovir and/or methylprednisolone.
本研究旨在通过群体药代动力学（PPK）分析，确定 allo-HSCT 受者中合并使用来特莫韦时影响伏立康唑血药浓度的因素。
回顾性收集伏立康唑谷浓度、患者特征、合并用药和实验室信息。采用 NONMEM 版本 7.4.3，采用具有交互作用的一阶条件估计法进行 PPK 分析。我们收集了 47 例患者 216 个时间点的稳态伏立康唑谷浓度数据。采用米氏方程非线性药代动力学模型描述稳态谷浓度与伏立康唑每日维持剂量之间的关系。在逐步进行协变量建模后，使用拟合优度图、病例删除诊断和 Bootstrap 方法对最终模型进行评估。
与未合用这些药物的患者相比，合用来特莫韦和甲泼尼龙的患者伏立康唑的最大消除率（V）分别增加了 1.72 倍和 1.30 倍，导致伏立康唑谷浓度降低。所开发的 PPK 模型能够很好地描述 allo-HSCT 受者的伏立康唑谷浓度曲线。模拟结果清楚地表明，当患者合用伏立康唑和来特莫韦和/或甲泼尼龙时，需要增加伏立康唑的每日剂量，以达到最佳的伏立康唑谷浓度（1-5 mg/L）。
制定个体化剂量调整方案对于实现最佳伏立康唑浓度至关重要，尤其是在 allo-HSCT 受者中合并使用来特莫韦和/或甲泼尼龙时。
