Anderson Brian J, Holford Nick H G
Department of Anaesthesiology, University of Auckland School of Medicine, New Zealand.
Drug Metab Pharmacokinet. 2009;24(1):25-36. doi: 10.2133/dmpk.24.25.
Growth and development are two major aspects of children not readily apparent in adults. Clearance in the paediatric population should be investigated using models that describe size, maturation and organ function influences. Size is the primary covariate and although lean body weight is argued as a better measure than total body weight, the use of different fractions of fat mass to explain how pharmacokinetic parameters vary with body composition has been proposed. Allometric scaling using an empiric power exponent of 3/4 is superior to scaling using body surface area. The sigmoid hyperbolic model has proven useful to describe maturation. An extra parameter that describes asymmetry can be incorporated into this model. These descriptors are used to illustrate creatinine, morphine and paracetamol clearance in children. Simultaneous investigation of pooled GFR, paracetamol and morphine data enabled testing for shared common features of maturation processes. Results suggest that GFR matures before paracetamol or morphine clearance, consistent with phase II conjugation processes that convert xenobiotics to water soluble forms that can subsequently be eliminated from the body through the renal system. The use of such mechanistic approaches improves understanding of paediatric pharmacokinetics; improving dosing predictions and allowing projection in exploratory drug development.
生长和发育是儿童的两个主要方面，在成人中不太明显。儿科人群的清除率应使用描述体型、成熟度和器官功能影响的模型进行研究。体型是主要协变量，尽管有人认为瘦体重比总体重是更好的衡量指标，但也有人提出使用不同比例的脂肪量来解释药代动力学参数如何随身体组成而变化。使用经验幂指数3/4的异速生长标度优于使用体表面积的标度。S形双曲线模型已被证明可用于描述成熟度。一个描述不对称性的额外参数可以纳入该模型。这些描述符用于说明儿童肌酐、吗啡和对乙酰氨基酚的清除率。对合并的肾小球滤过率、对乙酰氨基酚和吗啡数据进行同时研究，能够测试成熟过程的共同特征。结果表明，肾小球滤过率在对乙酰氨基酚或吗啡清除之前成熟，这与II期结合过程一致，该过程将外源性物质转化为水溶性形式，随后可通过肾脏系统从体内消除。使用这种机制方法可增进对儿科药代动力学的理解；改善剂量预测并在探索性药物开发中进行预测。
