应用蒙特卡洛模拟探索不同CYP2C19基因型侵袭性真菌感染患者的伏立康唑最佳用药方案

Use of Monte Carlo simulation to estimate the influence of CYP2C19 polymorphism on dosage regimen of voriconazole in patients with invasive fungal infection

目的:根据药动/药效(PK/PD)理论应用仿真模拟评价侵袭性真菌感染患者CYP2C19基因多态性对伏立康唑(VRC)用药方案的影响,促进个体化用药。方法:查找已发表的VRC药动学资料,采用蒙特卡洛模拟评估不同的CYP2C19基因型患者分别在接受不同的VRC给药方案下可能达到的稳态谷浓度水平及其概率分布,进而找出最优给药方案。每种给药方案模拟10 000例次。结果:快代谢基因型(EMs)患者给予VRC300 mg/q12 h口服(po)或200 mg/q12 h静滴(iv);中间代谢基因型(IMs)患者给予100 mg/q12 h po或100 mg/q12 h iv;慢代谢基因型(PMs)患者给予50 mg/q12 h po或50 mg/q12 h iv时稳态谷浓度分布于推荐谷浓度范围(0.5~3 mg·L^(-1))内的中靶概率(PTA)最大(均超过85%)且高于3 mg·L^(-1)的PTA最小(均小于10%),为最佳给药方案。结论:临床应根据患者CYP2C19基因型来个体化制定VRC的用药方案,以此确保治疗的安全性和有效性。

OBJECTIVE To estimate the influence of CYP2C19 polymorphism on dosage regimen of voriconazole（VRC）in patients with invasive fungal infection by simulation approach according to pharmacokinetics/pharmacodynamics（PK/PD）and to optimize dosage individualization.METHODS Pharmacokinetic data of VRC were obtained from the published papers.Monte Carlo simulation was carried to evaluate the level of steady state trough concentration and its probability distribution in patients with different CYP2C19 genotypes under different VRC regimens.The optimal dosage regimen was selected based on the simulation results.A total of 10 000 virtual patients were simulated in each regimen.RESULTS There was maximum（〉85%）probability of target attainment（PTA）that steady state trough concentration of VRC within the recommend range（0.5-3 mg·L^（-1））and minimum（〈10%）PTA over 3 mg·L^（-1）,while extensive metabolizers（EMs）were treated with300 mg/q12 h po or 200 mg/q12 h iv,and intermediate metabolizers（IMs）were treated with 100 mg/q12 h po or 100 mg/q12 h iv,and poor metabolizers（PMs）were treated with 50 mg/q12 h po or 50 mg/q12 h ivindividually,which was the optimization regimen for patients with different genotypes.CONCLUSION The clinical dosage regimen of VRC should be individualized based on the CYP2C19 genotype of patient to ensure the safety and efficacy of the treatment.