应用蒙特卡洛模型优化氟康唑在低体重早产儿中的给药方案

摘要：目的 应用蒙特卡洛模型优化氟康唑在低体重早产儿中给药方案，为个体化给药提供参考。方法 根据胎龄、体重及血肌酐对低体重早产儿进行分组，结合氟康唑对白念珠菌、近平滑念珠菌、热带念珠菌的最低抑菌浓度(MIC)的分布情况，以及氟康唑在低体重早产儿中的群体药动学参数，应用Crystal Ball 11.1.2.2软件对不同组的不同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 当感染真菌MIC值≤2μg/mL，氟康唑给药剂量6mg/(kg·d)时，PTA>90%，MIC值≥4μg/mL时，则需要适当增加给药剂量以满足治疗效果。当MIC值≤1μg/mL时，3mg/(kg·d)可满足治疗效果。对于超早期早产儿，氟康唑给药剂量6mg/(kg·d)可以满足MIC值≤4μg/mL治疗效果。对于28周以后早产儿，只有当血肌酐正常或大于正常值时，氟康唑给药剂量6mg/(kg·d)可以满足MIC为4μg/mL治疗效果。血肌酐低于正常值者，应适当增加该药剂量。氟康唑3mg/(kg·d)治疗白念珠菌均可满足CFR>90%，而对于热带念珠菌治疗，氟康唑6mg/(kg·d)才能满足CFR>90%，但对于近平滑念珠菌治疗，血肌酐低于正常值者，则需要增加氟康唑剂量。对于超早产儿，血肌酐正常或大于正常值，氟康唑6mg/(kg·d)基本能满足CFR>90%，而对于28周以后，血肌酐正常的早产儿，氟康唑9mg/(kg·d)以上才能满足CFR>90%，血肌酐高于正常值者，应用氟康唑6mg/(kg·d)足以满足CFR>90%。结论 氟康唑6mg/(kg·d)给药剂量基本能满足低体重早产儿血肌酐正常或高于正常者的治疗需要，但PTA值受胎龄、体重、血肌酐的影响，CFR值与病原菌MIC分布有关；因此个体到达理想治疗效果，应结合群体药动学与蒙特卡洛模型，以实现个体化给药方案。

Optimization of dosage regimens of fluconazole by Monte Carlo models in low-weight premature infants

Abstract Objective To optimize fluconazole administration in low-weight premature infants by Monte-Carlo models and to provide a reference for individualized administration of fluconazole in low-weight preterminfants. Methods According to gestational age, weight, and serum creatinine combined with the distribution ofminimum inhibitory concentration (MIC) of fluconazole against C. albicans, C. parapsilosis, and C. tropicalis, andthe population pharmacokinetic parameters of fluconazole in low-weight preterm infants, Crystal Ball 11.1.2.2 wasapplied. We performed Monte Carlo simulation (MCS) on different dosage regimens of different groups, using theprobability of target attainment (PTA) and cumulative fraction of response (CFR) as evaluation indicators. ResultsWhen the MIC value of the infected fungus was lower than 2μg/mL and the dose of fluconazole was 6mg/(kg·d), PTAcould reach above 90%. When the MIC value was higher than 4μg/mL, it was necessary to appropriately increasethe dose to obtain treatment effects. The dose of 3mg/(kg·d) could only meet the therapeutic effect when the MICvalue was≤1μg/mL. When MIC≤1μg/mL, 3mg/(kg·d) could satisfy the therapeutic effect. For extremely preterminfants, fluconazole dose of 6mg/(kg·d) could meet the therapeutic effect of MIC≤4μg/mL. For preterm infants after28 weeks, the MIC of 4μg/mL was satisfied with fluconazole dose of 6mg/(kg·d) only when the serum creatinine wasnormal or higher than normal. If the serum creatinine was lower than the normal value, the dosage of this medicineshould be increased appropriately. For the treatment of C. albicans, 3mg/(kg·d) fluconazole could meet the criterionof CFR>90%, while for the treatment of C. tropicalis, 6mg/(kg·d) fluconazole could meet the criterion of CFR>90%.But for the treatment of C. parapsilosis, when serum creatinine was lower than normal, it was necessary to increasethe dose of fluconazole. For preterm infants with normal or higher serum creatinine, 6mg/(kg·d) fluconazole couldmeet the criterion of CFR>90%, while for preterm infants with normal serum creatinine after 28 weeks, 9mg/(kg·d) orcould meet the criterion of CFR>90%, and for preterm infants with higher serum creatinine, 6mg/(kg·d) fluconazole issufficient to meet the criterion of CFR>90%. Concusion The 6mg/(kg·d) dose of fluconazole could basically meetthe treatment needs of low weight premature infants with normal or higher serum creatinine. However, PTA value wasaffected by gestational age, body weight, and serum creatinine, and the CFR value was related to the MIC distributionof pathogenic bacteria. Therefore, to achieve the ideal therapeutic effect of individuals, population pharmacokineticsand Monte Carlo models should be combined to realize individual drug delivery scheme.