Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
Br J Pharmacol. 2009 Jul;157(6):907-21. doi: 10.1111/j.1476-5381.2009.00267.x. Epub 2009 Jun 5.
The principles of inter-species dose extrapolation are poorly understood and applied. We provide an overview of the principles underlying dose scaling for size and dose adjustment for size-independent differences. Scaling of a dose is required in three main situations: the anticipation of first-in-human doses for clinical trials, dose extrapolation in veterinary practice and dose extrapolation for experimental purposes. Each of these situations is discussed. Allometric scaling of drug doses is commonly used for practical reasons, but can be more accurate when one takes into account species differences in pharmacokinetic parameters (clearance, volume of distribution). Simple scaling of drug doses can be misleading for some drugs; correction for protein binding, physicochemical properties of the drug or species differences in physiological time can improve scaling. However, differences in drug transport and metabolism, and in the dose-response relationship, can override the effect of size alone. For this reason, a range of modelling approaches have been developed, which combine in silico simulations with data obtained in vitro and/or in vivo. Drugs that are unlikely to be amenable to simple allometric scaling of their clearance or dose include drugs that are highly protein-bound, drugs that undergo extensive metabolism and active transport, drugs that undergo significant biliary excretion (MW > 500, ampiphilic, conjugated), drugs whose targets are subject to inter-species differences in expression, affinity and distribution and drugs that undergo extensive renal secretion. In addition to inter-species dose extrapolation, we provide an overview of dose extrapolation within species, discussing drug dosing in paediatrics and in the elderly.
种间剂量外推的原则理解和应用都很差。我们提供了一个概述的原则，为大小和大小无关的差异剂量调整缩放的基础。在三种主要情况下需要缩放剂量：临床试验中首次人体剂量的预期，兽医实践中的剂量外推以及实验目的的剂量外推。讨论了每种情况。出于实际原因，药物剂量的比例缩放通常是常用的，但如果考虑到药代动力学参数（清除率，分布体积）的物种差异，则可以更准确。对于某些药物，简单的药物剂量缩放可能会产生误导；校正蛋白结合，药物的物理化学性质或生理时间的物种差异可以改善缩放。然而，药物转运和代谢以及剂量-反应关系的差异可以抵消大小的影响。出于这个原因，已经开发了一系列建模方法，这些方法将体内模拟与体外和/或体内获得的数据结合在一起。不太可能对其清除率或剂量进行简单比例缩放的药物包括高度结合蛋白的药物，广泛代谢和主动转运的药物，经历显著胆汁排泄的药物（MW> 500，两亲，共轭） ），其靶标在物种间表达，亲和力和分布上存在差异的药物以及经历广泛肾分泌的药物。除了种间剂量外推，我们还概述了种内剂量外推，讨论了儿科和老年人的药物剂量。
