Abstract：
The dosing of fluconazole for young infants remains empirical because of the limited pharmacokinetic (PK) data. We aimed to establish a population PK model and assess the systematic exposure-response of commonly used regimens of fluconazole in Chinese infants. We included infants with a postnatal age of less than 120 days and received intravenous fluconazole. Both scheduled and scavenged plasma samples were collected, and fluconzaole concentration was determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using Phoenix NLME, and then Monte Carlo simulation was conducted to predict the probability of target attainment (PTA) of empirically used regimens of both prophylactic and therapeutic purposes. Based on 304 plasma samples from 183 young infants, fluconazole concentration data was best described by a one-compartment model with first-order elimination. Gestational Age (GA), postnatal age (PNA), and body weight (BW) were included in the final model as CL = 0.02*(GA/214)2.77*(PNA/13)0.24*exp(nCL); V = 1.56*(BW/1435)0.90*exp(nV). Model validation revealed the final model had qualified stability and acceptable predictive properties. Monte Carlo simulation indicated that under the same minimum inhibitory concentration (MIC) value and administration regimen, PTA decreased with GA and PNA. The commonly used prophylactic regimens can meet the clinical need, while higher doses might be needed for treatment of invasive candidiasis. This population PK model of fluconazole discriminated the impact of GA and PNA on CL and BW on V. Dosing adjustment was needed according to the GA and PNA of infants to achieve targeted exposures.
摘要：
由于药代动力学（PK）数据有限，因此对年轻婴儿的氟康唑剂量仍是经验性的。我们旨在建立人群PK模型，并评估中国婴儿常用氟康唑治疗方案的系统暴露反应。我们纳入了出生后年龄小于120天并接受静脉注射氟康唑的婴儿。收集计划和清除的血浆样本，和氟康唑浓度通过验证的超高效液相色谱-串联质谱法测定。使用凤凰NLME进行人口PK分析，然后进行蒙特卡洛模拟以预测预防和治疗目的的经验使用方案的目标达到（PTA）的概率。根据183名年轻婴儿的304份血浆样本，氟康唑浓度数据最好通过一阶消除的单室模型描述.妊娠年龄（GA），出生后年龄（PNA），和体重(BW)包括在最终模型中,CL=0.02*(GA/214)2.77*(PNA/13)0.24*exp(nCL);V=1.56*(BW/1435)0.90*exp(nV)。模型验证表明最终模型具有合格的稳定性和可接受的预测特性。蒙特卡罗模拟表明,在相同的最小抑菌浓度(MIC)值和给药方案下,PTA随GA和PNA降低。常用的预防方案可以满足临床需要，而侵袭性念珠菌病的治疗可能需要更高的剂量。氟康唑的这种群体PK模型区分了GA和PNA对CL和BW对V的影响。需要根据婴儿的GA和PNA调整剂量以实现有针对性的暴露。
