应用蒙特卡洛模拟法评估伏立康唑临床给药方案

Clinical Dosage Regimens of Voriconazole Evaluated by Monte Carlo Simulation

目的:为伏立康唑临床个体化用药提供参考。方法:汇总伏立康唑对烟曲霉和白色念珠菌的最低抑菌浓度(MIC)分布情况,以及伏立康唑在不同人群中的药动学参数,采用水晶球软件11.1.2.4对同一人群不同给药方案和不同人群同一给药方案进行蒙特卡洛模拟(MCS),以达标概率(PTA)和累积反应分数(CFR)为评价指标。结果:当免疫功能低下儿童的给药剂量为4、6 mg/kg时,MIC≤0.125 mg/L即可满足PTA>90%;当给药剂量增加至8 mg/kg时,MIC≤0.25 mg/L才可满足PTA>90%。对于应用相同给药方案(4 mg/kg)的不用人群而言,免疫功能低下青少年的MIC≤0.25 mg/L,健康成年人、造血干细胞移植患者、免疫功能低下成年人的MIC≤0.5 mg/L时,可满足PTA>90%。免疫功能低下儿童不同给药剂量(4、6、8 mg/kg)以及给药剂量同为4 mg/kg的不同人群(免疫功能低下青少年、健康成年人、造血干细胞移植患者、免疫功能低下成年人)对烟曲霉的CFR值分别为42.53%、58.41%、77.74%、70.16%、89.40%、93.72%、95.42%,对白色念珠菌的CFR值分别为96.68%、97.13%、97.94%、97.54%、98.07%、98.28%、98.35%。结论:上述纳入研究的不同人群的各种给药方案均能有效控制白色念珠菌感染,而对于免疫功能低下儿童和青少年则需适当增加给药剂量以满足烟曲霉感染临床治疗的需要。

OBJECTIVE： To provide reference for clinical individual medication of voriconatole. METHODS： The distribution of MIC of voriconazole to Aspergillus fumigatus and Candida albicans were summarized as well as the pharmacokinetic parameters of voriconazole in different populations. Using probability of target attainment （PTA） and cumulative fraction of response （CFR） as indexes, crystal ball software 11.1.2.4 was used for Monte Carlo simulation of different dosage regimens of same population and same dosage regimen of different populations. RESULTS ： For children with impaired immunity, when the drug doses of were 4, 6 mg/kg and MIC was lower than 0.125 mg/L, PTA was higher than 90% ; when the drug doses was increased to 8 mg/kg and MIC was lower than 0.125 rag/L, PTA was higher than 90%. For different populations receiving same dosage regimens （4 mg/kg）, MIC of teenagers with impaired immunity was lower than 0.25 mg/L and those of healthy adults, patients underwent hematopoietic stem cell transplantation and adults with impaired immunity were all lower than 0.5 mg/L, PTA was higher than 90%. CFR to A. fumigatus were 42.53%, 58.41%, 77.74%, 70.16%, 89.40%, 93.72%, 95.42% and CFR to C. albicans were 96.68%, 97.13%, 97.94%, 97.54%, 98.07%, 98.28%, 98.35% among children with impaired immunity receiving different drug doses （4, 6, 8 mg/kg） and dif- ferent populations receiving drug dose of 4 mg/kg （teenagers with impaired immunity, healthy adults, patients underwent hematopoietic stem cell transplantation, adults with impaired immunity）. CONCLUSIONS： Various dosage regimens of different populations included in this study could effectively control C. albicans infection. It is necessary to increase the drug dose of children and teenagers with impaired immunity in order to meet the needs ofA. fumigatus infection treatnaent.