Björkman Sven
Hospital Pharmacy, Malmö University Hospital, Malmö and Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Br J Clin Pharmacol. 2005 Jun;59(6):691-704. doi: 10.1111/j.1365-2125.2004.02225.x.
To create a general physiologically based pharmacokinetic (PBPK) model for drug disposition in infants and children, covering the age range from birth to adulthood, and to evaluate it with theophylline and midazolam as model drugs.
Physiological data for neonates, 0.5-, 1-, 2-, 5-, 10- and 15-year-old children, and adults, of both sexes were compiled from the literature. The data comprised body weight and surface area, organ weights, vascular and interstitial spaces, extracellular body water, organ blood flows, cardiac output and glomerular filtration rate. Tissue: plasma partition coefficients were calculated from rat data and unbound fraction (f u) of the drug in human plasma, and age-related changes in unbound intrinsic hepatic clearance were estimated from CYP1A2 and CYP2E1 (theophylline) and CYP3A4 (midazolam) activities in vitro. Volume of distribution (V dss), total and renal clearance (CL and CL R) and elimination half-life (t(1/2)) were estimated by PBPK modelling, as functions of age, and compared with literature data.
The predicted V dss of theophylline was 0.4-0.6 l kg(-1) and showed only a modest change with age. The median prediction error (MPE) compared with literature data was 3.4%. Predicted total CL demonstrated the time-course generally reported in the literature. It was 20 ml h(-1) kg(-1) in the neonate, rising to 73 ml h(-1) kg(-1) at 5 years and then decreasing to 48 ml h(-1) kg(-1) in the adult. Overall, the MPE was - 4.0%. Predicted t(1/2) was 18 h in the neonate, dropping rapidly to 4.6-7.2 h from 6 months onwards, and the MPE was 24%. The predictions for midazolam were also in good agreement with literature data. V dss ranged between 1.0 and 1.7 l kg(-1) and showed only modest change with age. CL was 124 ml h(-1) kg(-1) in the neonate and peaked at 664 ml h(-1) kg(-1) at 5 years before decreasing to 425 ml h(-1) kg(-1) in the adult. Predicted t(1/2) was 6.9 h in the neonate and attained 'adult' values of 2.5-3.5 h from 1 year onwards.
A general PBPK model for the prediction of drug disposition over the age range neonate to young adult is presented. A reference source of physiological data was compiled and validated as far as possible. Since studies of pharmacokinetics in children present obvious practical and ethical difficulties, one aim of the work was to utilize maximally already available data. Prediction of the disposition of theophylline and midazolam, two model drugs with dissimilar physicochemical and pharmacokinetic characteristics, yielded results that generally tallied with literature data. Future use of the model may demonstrate further its strengths and weaknesses.
建立一个基于生理学的通用药代动力学（PBPK）模型，用于描述从出生到成年各年龄段婴幼儿及儿童的药物处置过程，并以茶碱和咪达唑仑作为模型药物对该模型进行评估。
从文献中收集了新生儿、0.5岁、1岁、2岁、5岁、10岁、15岁儿童以及成年人的生理学数据，涵盖男女两性。这些数据包括体重、体表面积、器官重量、血管和间质间隙、细胞外体液、器官血流量、心输出量以及肾小球滤过率。根据大鼠数据和药物在人血浆中的游离分数（fu）计算组织：血浆分配系数，并根据体外CYP1A2和CYP2E1（茶碱）以及CYP3A4（咪达唑仑）的活性估算游离内在肝清除率随年龄的变化。通过PBPK建模估算分布容积（Vdss）、总清除率和肾清除率（CL和CLR）以及消除半衰期（t(1/2)），将其作为年龄的函数，并与文献数据进行比较。
茶碱的预测Vdss为0.4 - 0.6 l kg(-1)，且随年龄变化不大。与文献数据相比，中位预测误差（MPE）为3.4%。预测的总CL呈现出文献中普遍报道的时间进程。新生儿的总CL为20 ml h(-1) kg(-1)，5岁时升至73 ml h(-1) kg(-1)，然后在成年人中降至48 ml h(-1) kg(-1)。总体而言，MPE为 - 4.0%。新生儿的预测t(1/2)为18小时，从6个月起迅速降至4.6 - 7.2小时，MPE为24%。咪达唑仑的预测结果也与文献数据高度一致。Vdss在1.0至1.7 l kg(-1)之间，随年龄变化不大。新生儿的CL为124 ml h(-1) kg(-1)，5岁时达到峰值664 ml h(-1) kg(-1)，然后在成年人中降至425 ml h(-1) kg(-1)。新生儿的预测t(1/2)为6.9小时，从1岁起达到“成人”值2.5 - 3.5小时。
提出了一个用于预测新生儿至青年成人年龄段药物处置的通用PBPK模型。尽可能收集并验证了生理学数据的参考来源。鉴于儿童药代动力学研究存在明显的实际和伦理困难，该研究的一个目标是最大限度地利用已有数据。对茶碱和咪达唑仑这两种理化性质和药代动力学特征不同的模型药物的处置预测结果总体上与文献数据相符。该模型的未来应用可能会进一步展示其优势和不足。
