The University of Manchester, Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.
Antimicrob Agents Chemother. 2010 Jun;54(6):2633-7. doi: 10.1128/AAC.01679-09. Epub 2010 Mar 22.
Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of micafungin in infants. Here, we describe the population pharmacokinetics of micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).
米卡芬净是一种棘白菌素类药物，对念珠菌属具有强大的活性。血液性念珠菌脑膜脑炎（HCME）是早产儿播散性念珠菌感染的常见并发症。HCME 的临床前模型表明，米卡芬净可能是该综合征的有效药物，但需要较高的基于体重的剂量。这促使我们进一步研究米卡芬净在婴儿中的安全性和药代动力学（PK）。在这里，我们描述了 47 例确诊或疑似播散性念珠菌病的婴儿的米卡芬净群体药代动力学，这些婴儿接受了 0.75、1.5、3、7、10 和 15 mg/kg 的米卡芬净。药物每天输注，在第一个给药间隔和稳态时采集样本。使用高效液相色谱法（HPLC）测量血清浓度。使用基于三分之四清除率和参数标准化为 70kg 成人的比例模型对数据进行建模。使用蒙特卡罗模拟估计药物暴露量。使用 D-最优设计理论确定最佳采样时间。比例模型对数据的拟合非常理想。米卡芬净的药代动力学呈线性。清除率和分布容积的体重标准化估计值接近先前描述的成人值。原始群体参数值可以在蒙特卡罗模拟中重现。每天 10mg/kg 的剂量可使 82.6%的患者的浓度-时间曲线下面积（AUC）与中枢神经系统（CNS）中真菌负荷最大下降相关。
