密克罗尼西亚联邦和马绍尔群岛共和国接受活动性或潜伏性耐多药结核病治疗的儿童中左氧氟沙星的药代动力学和剂量
Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands.
作者信息
Mase Sundari R, Jereb John A, Gonzalez Daniel, Martin Fatma, Daley Charles L, Fred Dorina, Loeffler Ann M, Menon Lakshmy R, Bamrah Morris Sapna, Brostrom Richard, Chorba Terence, Peloquin Charles A
机构信息
From the *Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia; †Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida; ‡Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; §Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; ¶North Bay Pediatrics, Vallejo, California; ‖Division of Mycobacterial and Respiratory Infections, National Jewish Health, Denver, Colorado; **TB/Leprosy Program, Federated States of Micronesia (FSM); ††Francis J. Curry International TB Center, San Francisco, California; and ‡‡Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida.
出版信息
Pediatr Infect Dis J. 2016 Apr;35(4):414-21. doi: 10.1097/INF.0000000000001022.
BACKGROUND
In the Federated States of Micronesia and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics were studied in children receiving directly observed once-daily regimens (10 mg/kg, age >5 years; 15-20 mg/kg, age ≤5 years) for either multidrug-resistant tuberculosis disease or latent infection after multidrug-resistant tuberculosis exposure, to inform future dosing strategies.
METHODS
Blood samples were collected at 0 (RMI only), 1, 2 and 6 hours (50 children, aged 6 months to 15 years) after oral levofloxacin at >6 weeks of treatment. Clinical characteristics and maximal drug concentration (Cmax) of levofloxacin, elimination half-life and area under the curve from 0 to 24 hours (AUC0-24 hours × μg/mL) were correlated to determine the optimal dosage and to examine associations. Population pharmacokinetics and target attainment were modeled. With results from the Federated States of Micronesia, dosages were increased in RMI toward the target Cmax for Mycobacterium tuberculosis, 8-12 µg/mL.
RESULTS
Cmax correlated linearly with per-weight dosage. Neither Cmax nor half-life was associated with gender, age, body mass index, concurrent medications or predose meals. At levofloxacin dosage of 15-20 mg/kg, Cmax ≥8 µg/mL was observed, and modeling corroborated a high target attainment across the ratio of the area under the free concentration versus time curve to minimum inhibitory concentration (fAUCss,0-24/MIC) values.
CONCLUSIONS
Levofloxacin dosage should be 15-20 mg/kg for Cmax ≥8 µg/mL and a high target attainment across fAUCss,0-24/MIC values in children ≥2 years of age.
背景
在密克罗尼西亚联邦以及随后的马绍尔群岛共和国（RMI），针对多药耐药结核病或多药耐药结核病暴露后的潜伏感染，对接受直接观察下每日一次给药方案（年龄>5岁，10mg/kg；年龄≤5岁，15 - 20mg/kg）的儿童进行了左氧氟沙星药代动力学研究，以指导未来的给药策略。
方法
在治疗6周以上口服左氧氟沙星后0（仅RMI）、1、2和6小时（50名年龄6个月至15岁的儿童）采集血样。将左氧氟沙星的临床特征、最大药物浓度（Cmax）、消除半衰期和0至24小时曲线下面积（AUC0 - 24小时×μg/mL）进行关联，以确定最佳剂量并检查相关性。建立群体药代动力学和目标达成模型。根据密克罗尼西亚联邦的结果，RMI将剂量增加至针对结核分枝杆菌的目标Cmax，即8 - 12μg/mL。
结果
Cmax与每体重剂量呈线性相关。Cmax和半衰期均与性别、年龄、体重指数、同时服用的药物或给药前饮食无关。在左氧氟沙星剂量为15 - 20mg/kg时，观察到Cmax≥8μg/mL，模型证实游离浓度与时间曲线下面积与最低抑菌浓度之比（fAUCss,0 - 24/MIC）值的目标达成率较高。
结论
对于2岁及以上儿童，左氧氟沙星剂量应为15 - 20mg/kg，以实现Cmax≥8μg/mL以及较高的fAUCss,0 - 24/MIC值目标达成率。
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