Predictive performance of a gentamicin population pharmacokinetic model in neonates receiving full-body hypothermia.
Predictive performance of a gentamicin population pharmacokinetic model in neonates receiving full-body hypothermia.
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DOI：
10.1097/ftd.0000000000000056
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发表时间：
2014-10
影响因子：
2.5
通讯作者：
Cohen-Wolkowiez M
中科院分区：
文献类型：
--
作者：
Sampson MR;Frymoyer A;Rattray B;Cotten CM;Smith PB;Capparelli E;Bonifacio SL;Cohen-Wolkowiez M
来自新生儿小型PK研究的群体药代动力学（popPK）模型通常不足以检测驱动给药的临床重要特征。外部验证这些模型至关重要。在本研究中，评价了庆大霉素popPK模型在接受低温治疗的新生儿中的预测性能。使用回顾性单机构（UCSF）数据集，在接受低温治疗的缺氧缺血性脑病新生儿中开发了先前发表的庆大霉素popPK模型。在UCSF（验证A）和杜克大学（验证B）的外部回顾性数据集中评价了该模型的预测性能。两个机构使用相同的低温方案，并收集相似的临床和PK数据。按照常规护理采集庆大霉素给药和样本。通过量化模型预测的准确性和精密度以及使用基于模拟的诊断来检测预测中的偏差来评估预测性能。分析了41例中位（范围）胎龄为40周（33-42）、出生体重为3.3 kg（1.9-4.6）的新生儿（验证A组18例，验证B组23例）和76份样本（55%谷值，分别在给药后24和36 h抽取33%和28%）。该模型充分预测了来自同一机构的庆大霉素浓度（验证A;中位平均倍数误差[AFE]=1.1，数值预测分布误差[NPDE] p值>0.05），但低于来自外部机构的预测浓度（验证B;中位AFE=0.6，NPDE p值<0.05）。该模型对同一机构的外部数据集表现出足够的预测性能，但对外部机构则没有。在新生儿popPK模型开发中，更大的样本量、使用来自多个机构的数据和外部评价可提高单机构研究中剂量建议的普遍性。
Population pharmacokinetic (popPK) models derived from small PK studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated. A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (UCSF) dataset. The predictive performance of this model was evaluated in an external retrospective dataset from UCSF (Validation A) and another from Duke University (Validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions. 41 neonates (18 Validation A, 23 Validation B) with median (range) gestational age of 40wks (33–42) and birth weight of 3.3kg (1.9–4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36h post dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (Validation A; median average fold error [AFE]=1.1 and numerical prediction distribution error [NPDE] p-value>0.05) but under-predicted concentrations from the outside institution (Validation B; median AFE=0.6 and NPDE p-value<0.05). The model demonstrated adequate predictive performance for an external dataset in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.