Hope William W, Seibel Nita L, Schwartz Cindy L, Arrieta Antonio, Flynn Patricia, Shad Aziza, Albano Edythe, Keirns James J, Buell Donald N, Gumbo Tawanda, Drusano George L, Walsh Thomas J
Pediatric Oncology Branch, NCI/NIH, CRC Room 1-5750, Bethesda, MD 20892-1100, USA.
Antimicrob Agents Chemother. 2007 Oct;51(10):3714-9. doi: 10.1128/AAC.00398-07. Epub 2007 Jul 16.
The echinocandins potentially have an important role in treatment of infections caused by Candida spp. and Aspergillus spp. in immunocompromised children. However, there are no population pharmacokinetic models of the echinocandins for pediatric patients. The safety and descriptive pharmacokinetics of micafungin in children were recently reported. However, a population pharmacokinetic model in children is needed in order to accurately determine the dosage of micafungin that produces an equivalent magnitude of drug exposure to that observed in adults. In order to explore the effect of weight on micafungin pharmacokinetics, a standard two-compartment pharmacokinetic model, a linear model, and an allometric power model were developed. For all three models, the fit to the data was excellent, with comparable measures of precision and bias. However, the superior log-likelihood value of the allometric power model suggested that it best reflected the data and was therefore chosen for a more detailed analysis of the magnitude and pattern of drug exposure which develop following the administration of micafungin. The allometric power model suggested that clearance in smaller children is higher than that predicted on the basis of weight alone. Consequently, a degree of dosage increase is required in smaller children to ensure comparable levels of drug exposure to those observed in larger children and adults. The allometric power model developed in this study enables identification of pediatric dosage regimens of micafungin which, based upon Monte Carlo simulations, result in equivalent drug exposures to those observed in adults, for which antifungal efficacy has been established.
棘白菌素类药物在免疫功能低下儿童的念珠菌属和曲霉属感染治疗中可能发挥重要作用。然而，目前尚无针对儿科患者的棘白菌素类药物群体药代动力学模型。最近有关于米卡芬净在儿童中的安全性及描述性药代动力学的报道。然而，为了准确确定能产生与成人相当药物暴露量的米卡芬净剂量，仍需要建立儿童群体药代动力学模型。为了探究体重对米卡芬净药代动力学的影响，开发了标准二室药代动力学模型、线性模型和异速幂模型。对于这三种模型，数据拟合效果均极佳，精度和偏差指标相当。然而，异速幂模型更高的对数似然值表明它最能反映数据，因此被选用于更详细地分析米卡芬净给药后药物暴露的程度和模式。异速幂模型表明，较小儿童的清除率高于仅基于体重预测的清除率。因此，较小儿童需要增加一定程度的剂量，以确保与较大儿童和成人有相当的药物暴露水平。本研究中开发的异速幂模型能够确定米卡芬净的儿科给药方案，基于蒙特卡洛模拟，该方案能产生与已确立抗真菌疗效的成人相当的药物暴露量。
