Dosage regimen design for pharmaceutical studies conducted in animals.
Dosage regimen design for pharmaceutical studies conducted in animals.
复制标题
在动物身上进行的药物研究的剂量方案设计。
DOI：
10.1002/jps.2600750906
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发表时间：
1986
影响因子：
3.8
通讯作者：
J. Mordenti
中科院分区：
文献类型：
--
作者：
J. Mordenti
不同动物品种给药方案的选择需要建立种间药代动力学等效性。药代动力学等效性可以根据暴露量（即，每个物种的相同峰值血清浓度）和暴露时间（即，在有限的给药间隔内，血清浓度-时间曲线下的相同面积）来定义。以头孢替肟[(6R,7R)-7-[2-（2-亚胺-4-噻唑-4-酰基）乙氧基氨基]- 8-氧-5-噻-1-氮杂比环][4.2.0]辛-2-烯-2-羧酸盐7(2)-(Z)-（o-甲基肟）]为模型化合物，通过为每种物种选择产生相似峰值血清浓度的剂量，建立了小鼠、大鼠、猴子、狗和人类的药代动力学等效性。在给药间隔24小时的血清浓度-时间曲线下，选择一种能产生等量面积的给药方案。动物体重与剂量和动物体重与给药计划的关系可以用幂方程Y = aWb很好地描述，其中Y为剂量变量，W为动物体重，log a为Y截距，b为log Y与log W曲线的斜率。从文献中获得14种抗肿瘤药物的毒理学数据。功率方程充分描述了大多数化合物的毒性剂量与动物体重之间的关系，也证明了功率方程在毒性研究中评估给药方案的效用。
The selection of dosage regimens for different animal species requires the establishment of pharmacokinetic equivalency between species. Pharmacokinetic equivalency can be defined in terms of the magnitude of exposure (i.e., an identical peak serum concentration in each species) and the duration of exposure (i.e., an identical area under the serum concentration-time curve in a finite dosing interval). Using ceftizoxime [(6R,7R)-7-[2-(2-imino-4-thiazolin-4-yl)glyoxylamido]- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 7(2)-(Z)-(O-methyl-oxime)] as a model compound, pharmacokinetic equivalency in mice, rats, monkeys, dogs, and humans was established by selecting a dose for each species that produced similar peak serum concentrations, and by selecting a dosage schedule for each species that produced an equivalent area under the serum concentration-time curve in a 24-h dosing interval. The relationships of animal weight to dose and animal weight to dosing schedule were well described by the power equation Y = aWb, where Y is the dosage variable, W is animal weight, log a is the y-intercept, and b is the slope obtained from the plot of log Y versus log W. Toxicology data for 14 antineoplastic agents were obtained from the literature. The power equation adequately described the relationship between toxic dose and animal weight for most of the compounds, demonstrating the utility of the power equation in the assessment of dosing regimens for toxicity studies as well.