Objective

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.

Methods

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.

Results

The maximum elimination rate (V_max) 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.

Conclusions

The development of individualized dose adjustment is critical to achieve optimal voriconazole concentration, especially among allo-HSCT recipients receiving concomitant letermovir and/or methylprednisolone.

中文翻译：

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莱特莫韦和/或甲基强的松龙合用对造血干细胞移植中伏立康唑药代动力学的影响：一项群体药代动力学研究

客观的

本研究的目的是在同种异体造血干细胞移植 (allo-HSCT) 受者中使用群体药代动力学 (PPK) 分析来确定影响莱特莫韦联合给药后伏立康唑血药浓度的因素。

方法

回顾性收集了以下数据：伏立康唑谷浓度、患者特征、伴随药物和实验室信息。PPK 分析使用 NONMEM ^® 7.4.3 版进行，使用具有交互作用的一阶条件估计方法。我们收集了 47 名患者在 216 个时间点的血浆伏立康唑稳态谷浓度数据。应用带有 Michaelis-Menten 方程的非线性药代动力学模型来描述稳态谷浓度与伏立康唑每日维持剂量之间的关系。在逐步协变量建模后，使用拟合优度图、病例删除诊断和引导方法评估最终模型。

结果

最大消除速率（V_最大患者伏立康唑）分别共同施用letermovir和甲泼尼龙明显高于患者共施用不这些药物更大的1.72和1.30倍，导致降低的伏立康唑谷浓度。开发的 PPK 模型充分描述了同种异体造血干细胞移植受者的伏立康唑谷浓度分布。模拟清楚地表明，当患者接受伏立康唑与莱特莫韦和/或甲基强的松龙治疗时，需要增加伏立康唑的每日剂量才能达到最佳伏立康唑谷浓度 (1-5 mg/L)。

结论

个体化剂量调整的发展对于实现最佳伏立康唑浓度至关重要，尤其是在同时接受莱特莫韦和/或甲基强的松龙的同种异体造血干细胞移植受者中。