Falcão A C, Fernández de Gatta M M, Delgado Iribarnegaray M F, Santos Buelga D, García M J, Dominguez-Gil A, Lanao J M
Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Portugal.
Eur J Clin Pharmacol. 1997;52(3):211-7. doi: 10.1007/s002280050276.
To determine population pharmacokinetic parameters of caffeine in premature neonates.
This population analysis was done using 145 serum concentration measurements gathered from 75 hospitalized patients during their routine clinical care. The data were analysed by use of NONMEM (mixed effects modeling) according to a one-compartment open model with either zero or first-order absorption and first-order elimination. The effect of a variety of developmental, demographic and clinical factors (gender, birth weight, current weight, gestational age, postnatal age, postconceptional age and concurrent treatment with phenobarbital and parenteral nutrition) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates.
The final pharmacostatistical model with influential covariates were as follows: clearance (m1.h-1) = 5.81-current weight (kg) + 1.22.postnatal age (weeks), multiplied by 0.757 if gestational age < or = 28 weeks and 0.836 if the current primary source of patients' nutrition is parenteral nutrition, and volume of distribution (ml) = 911.current weight (kg). The inter-individual variability in clearance and the residual variability, expressed as coefficients of variation, were 14.8%, and 18.44%, respectively. Due to the lack of information on the data set we were unable to characterize the interindividual variability for volume of distribution.
In this study, which involved on average only two serum concentrations of caffeine per patient, the use of NONMEM gave us significant and consistent information about the pharmacokinetic profile of caffeine when compared with available bibliographic information. Additionally, parenteral nutrition and low gestational age (< or = 28 weeks) may even come to be considered as risk factors, and their presence may serve as an indicator of the need for periodic monitoring of caffeine concentrations in premature infants.
确定咖啡因在早产儿中的群体药代动力学参数。
本群体分析使用了在75例住院患者常规临床护理期间收集的145份血清浓度测量值。根据具有零级或一级吸收以及一级消除的单室开放模型，使用NONMEM（混合效应建模）对数据进行分析。研究了各种发育、人口统计学和临床因素（性别、出生体重、当前体重、胎龄、出生后年龄、孕龄以及苯巴比妥和肠外营养的同时治疗）对清除率和分布容积的影响。向前选择和向后排除回归确定了显著的协变量。
具有影响协变量的最终药效统计模型如下：清除率（m1.h-1）=5.81-当前体重（kg）+1.22×出生后年龄（周），如果胎龄≤28周则乘以0.757，如果患者当前的主要营养来源是肠外营养则乘以0.836，分布容积（ml）=911×当前体重（kg）。以变异系数表示的清除率个体间变异性和残差变异性分别为14.8%和18.44%。由于数据集中缺乏相关信息，我们无法描述分布容积的个体间变异性。
在本研究中，平均每位患者仅进行了两次咖啡因血清浓度检测，与现有文献信息相比，使用NONMEM为我们提供了有关咖啡因药代动力学特征的重要且一致的信息。此外，肠外营养和低胎龄（≤28周）甚至可能被视为危险因素，它们的存在可作为早产儿需要定期监测咖啡因浓度的指标。
