伏立康唑的群体药代动力学和 CYP2C19 多态性与肾移植受者优化给药方案。
Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients.
机构信息
Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Institute of Clinical Pharmacy, Central South University, Changsha, Hunan, 410011, China.
出版信息
Br J Clin Pharmacol. 2018 Jul;84(7):1587-1597. doi: 10.1111/bcp.13595. Epub 2018 May 6.
AIMS
The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections.
METHODS
A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model.
RESULTS
A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily.
CONCLUSIONS
Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.
目的
本研究旨在描述肾移植受者伏立康唑的药代动力学特征，并确定显著影响药代动力学参数的因素。我们还旨在为发生侵袭性真菌感染的患者探索最佳的给药方案。
方法
前瞻性纳入 105 例患者（342 个浓度）进行群体药代动力学分析。使用 Phoenix NLME 软件建立非线性混合效应模型。基于最终模型进行给药模拟。
结果
采用一室模型加一级吸收和消除来描述伏立康唑的药代动力学。清除率、分布容积和口服生物利用度的群体估计值分别为 2.88 l·h-1、169.3 l 和 58%。细胞色素 P450 基因（CYP）2C19*2、3 和17 变体的等位基因频率分别为 29.2%、5.2%和 0.5%。CYP2C19 基因型对清除率有显著影响。弱代谢者的伏立康唑谷浓度明显高于中代谢者和强代谢者。分布容积随体重增加而增加。移植后 1 个月内口服生物利用度显著降低，但随术后时间延长而增加。给药模拟表明，在术后早期，弱代谢者可采用 150 mg 静脉注射或 250 mg 口服，每日 2 次；中代谢者可采用 200 mg 静脉注射或 350 mg 口服，每日 2 次；强代谢者可采用 300 mg 静脉注射，每日 2 次。
结论
结合 CYP2C19 基因型和术后时间来确定初始伏立康唑给药方案，随后进行治疗药物监测，有助于为发生侵袭性真菌感染的肾移植患者推进个体化治疗。
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