THE ALLOMETRIC APPROACH FOR INTERSPECIES SCALING OF PHARMACOKINETICS AND TOXICITY OF ANTICANCER DRUGS
THE ALLOMETRIC APPROACH FOR INTERSPECIES SCALING OF PHARMACOKINETICS AND TOXICITY OF ANTICANCER DRUGS
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DOI：
10.1111/j.1440-1681.1995.tb01949.x
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发表时间：
1995-11-01
影响因子：
2.9
通讯作者：
PAXTON, JW
中科院分区：
文献类型：
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作者：
PAXTON, JW
1.跨动物物种进行外推或“缩放”的依据是它们在解剖学、生理学和生物化学方面的基本相似性。19世纪和20世纪初进行的研究得出了本尼迪克特著名的老鼠对大象的曲线图，该曲线图显示基础代谢率的对数与体重(W)的对数产生了一条斜率为0.76的直线。从那时起，很明显，许多其他生理变量(Y)表现出类似的关系，其可以由一般的异速生长方程Y=W-α(β)来表示；其中，β是对数-对数曲线的斜率，而α是y轴上的截距。许多药物的清除度、分布体积等主要药动学参数也与W有相似的关系。这种经验性方法不需要很强的数学背景，并且提供了一种从临床前动物数据预测患者体内抗癌药物动力学的相对简单的方法。物种间药物代谢在质量和数量上的重大差异可能是使用动物作为患者药物毒性和动力学预测指标的最大复杂因素。尽管如此，异速生长方法对于在I期试验中估计一些药物的更合适的起始剂量是有用的，这可能会在升级步骤中产生潜在的节省，并最大限度地增加个人接受的剂量具有潜在治疗价值的机会。
1. The rationale for extrapolation or 'scaling' across animal species is based on their underlying anatomical, physiological and biochemical similarities.2. Research carried out in the 19th and early 20th century resulted in Benedict's famous 'mouse-to-elephant' graph which showed that the log of the basal metabolic rate plotted against the log of bodyweight (W) produced a straight line with a slope of 0.76. Since then it has become apparent that a number of other physiological variables (Y) exhibit a similar relationship which can be represented by the general allometric equation, Y = W-alpha(beta); where beta is the slope of the log-log plot and alpha is the intercept on the y axis.3. The major pharmacokinetic parameters such as clearance and volume of distribution of many drugs are also related to W in a similar manner.4. This empirical approach does not require a strong mathematical background and offers a relatively simple method of predicting the kinetics of anti-cancer drugs in patients from pre-clinical animal data.5. The occurrence of major qualitative and quantitative differences in the metabolism of drugs between species is probably the single greatest complicating factor in the use of animals as predictors of drug toxicity and kinetics in patients.6. Despite this, the allometric approach is useful for allowing the estimation of a more appropriate starting dose for some drugs in a Phase I trial, which might result in potential savings in escalation steps and maximize the chance that the dose which an individual receives has the potential for therapeutic value.