Population Model of Serum Creatinine as Time-Dependent Covariate in Neonates
Population Model of Serum Creatinine as Time-Dependent Covariate in Neonates
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DOI：
10.1208/s12248-021-00612-x
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发表时间：
2021-06-17
期刊：
影响因子：
4.5
通讯作者：
Allegaert, Karel
中科院分区：
文献类型：
--
作者：
Krzyzanski, Wojciech;Smits, Anne;Allegaert, Karel
血清肌酐（sCr）是估算肾小球滤过率（GFR）的常用生物标志物，因此广泛用作肾排泄药物群体药代动力学模型的协变量。在新生儿中，sCr在出生后的前几周内动态变化。由于血液采样数量和体积有限，缺失协变量是新生儿药代动力学建模中的常见问题。这项工作的目的是开发一个简约的人口模型，描述新生儿sCr的时间进程，旨在纳入各种药物的药代动力学模型，其中sCr值稀疏或缺失。模型开发的数据包括1080例胎龄为24-42周的新生儿的sCr测量值。该模型基于sCr的药代动力学模型，涉及GFR、肌酐从肾小管回流和尿流量。年龄是解释sCr受试者间变异性的唯一协变量。该模型充分描述了sCr时间过程的不同特征，例如峰值和下降至平台。对于GA为35周的新生儿，出生时sCr的典型值为0.584 mg/dL，峰值（0.794 mg/dL）出现在出生后2.3天，大约在24.7天后达到0.255 mg/dL的平台。模型模拟显示，在出生后年龄相似的新生儿中，sCr随着GA的增加而降低。总之，我们的模型设计为全随机效应药代动力学模型的一部分，其中sCr是显著协变量。
Serum creatinine (sCr) is a commonly measured biomarker to estimate glomerular filtration rate (GFR) and therefore widely used as a covariate in population pharmacokinetic models of renally excreted drugs. In neonates, sCr dynamically changes during the first few weeks after birth. Missing covariates are a common problem in pharmacokinetic modeling of neonates due to the limited availability of blood sampling in number and volume. The objective of this work is to develop a parsimonious population model describing time courses of sCr in neonates with the intent to be incorporated into pharmacokinetic models of various drugs where sCr values are sparse or missing. The data for model development consisted of sCr measurements in 1080 newborns with a gestational age of 24-42 weeks. The model is based on a pharmacokinetic model of sCr that involves GFR, backflow of creatinine from the renal tubules, and urinary flow. Gestational age is the only covariate explaining between-subject variability of sCr. The model adequately describes distinct features of the sCr time course such as a peak and decline to a plateau. For a neonate with a GA of 35 weeks, the typical value of sCr at birth was 0.584 mg/dL, the peak (0.794 mg/dL) occurred 2.3 days after birth, to reach a plateau of 0.255 mg/dL approximately after 24.7 days. Model simulations reveal that in neonates with a similar postnatal age, sCr decreases with increasing GA. In summary, our model is designed to be a part of full random effects pharmacokinetic models where sCr is a significant covariate.