使用早产儿的血浆和干血斑样本确定甲硝唑的群体药代动力学和发育药代动力学。
Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.
机构信息
From the *Department of Pediatrics, Duke University; †Duke Clinical Research Institute, Durham, NC; ‡Wichita Medical Research and Education Foundation, Wichita, KS; §Division of Infectious Diseases, CHOC-Children's Hospital of Orange County, Orange, CA; ¶Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Vanderbilt University Medical Center, Nashville, TN; ‖EMMES Corporation, Rockville, MD; **Department of Pediatrics, University of Missouri-Kansas City School of Medicine and the Division of Pediatric Pharmacology and Therapeutic Innovation, The Children's Mercy Hospital, Kansas City, MO; ††Department of Pediatric Pharmacology, University of California, San Diego, CA; and ‡‡Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.
出版信息
Pediatr Infect Dis J. 2013 Sep;32(9):956-61. doi: 10.1097/INF.0b013e3182947cf8.
BACKGROUND
Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections.
METHODS
We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N = 3) study using population PK modeling (NONMEM). Monte Carlo simulations (N = 1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated.
RESULTS
Twenty-four premature infants (111 plasma and 51 dried blood spot samples) were enrolled: median (range) gestational age at birth 25 (23-31) weeks, postnatal age 27 (1-82) days, postmenstrual age 31 (24-39) weeks and weight 740 (431-1466) g. Population clearance (L/h/kg) was 0.038 × (postmenstrual age/30) and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and dried blood spot samples. Metabolic ratios correlated with clearance.
CONCLUSION
Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using postmenstrual age-based dosing.
背景
由于甲硝唑在早产儿中的药代动力学（PK）数据有限，导致了各种剂量建议。甲硝唑的替代疗效指标定义不明确，因此旨在超过导致腹腔内感染的病原体的最低抑菌浓度。
方法
我们使用群体 PK 建模（NONMEM）在一项开放性、PK、多中心（N=3）研究中评估了≤32 周胎龄婴儿的甲硝唑 PK，使用血浆和干血斑样本。蒙特卡罗模拟（N=1000 个虚拟受试者）用于评估替代疗效指标。计算了母体和代谢物的代谢比。
结果
共纳入 24 名早产儿（111 份血浆和 51 份干血斑样本）：出生时的中位（范围）胎龄为 25（23-31）周，生后年龄为 27（1-82）天，校正胎龄为 31（24-39）周，体重为 740（431-1466）g。人群清除率（L/h/kg）为 0.038×（校正胎龄/30），分布容积（L/kg）为 0.93。血浆和干血斑样本的 PK 参数估计值和精密度相似。代谢比与清除率相关。
结论
模拟结果表明，新生儿重症监护病房中的大多数婴儿（>80%）使用基于校正胎龄的剂量方案将达到替代疗效指标。
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