Mixed effect modeling of sumatriptan pharmacokinetics during drug development .1. Interspecies allometric scaling
Mixed effect modeling of sumatriptan pharmacokinetics during drug development .1. Interspecies allometric scaling
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DOI：
10.1023/a:1025728028890
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发表时间：
1997-04-01
期刊：
影响因子：
--
通讯作者：
Bye, A
中科院分区：
文献类型：
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作者：
Cosson, VF;Fuseau, E;Bye, A
异速生长缩放是对药代动力学参数和体型（通常是体重）之间关系的实证检查，但它也可能涉及代谢药物的脑重量。在所有物种中，舒马曲坦的蛋白质结合相似（14-16%），其代谢途径经历涉及单胺氧化酶 A 同工酶的广泛氧化脱氨基作用。这些跨物种的相似性表明异速生长分析可能具有相关性。毒代动力学数据是在动物药代动力学研究中从大鼠、怀孕兔和狗身上收集的，其中舒马普坦分别以 5 mg/kg、0.25 mg/kg 和 1 mg/kg 的剂量静脉注射给动物。使用混合效应建模（群体）方法一步汇集并分析动物数据。任何物种的预测动力学参数都接近物种的观测值。人的总清除率为 77 L/hr vs. 80 L/hr，稳态下的分配体积为 137 L/hr vs. 119 L。与两步法相比，混合效应建模方法的价值得到了证明，特别是在模型中包含协变量来描述动物状态（例如怀孕）的可能性。了解药物的动物动力学、动力学和代谢有助于最佳和快速的开发。设计首次人体研究的宝贵信息可能会基于新药临床前和正在进行的非临床评估期间收集的所有信息，加快更具创造性的数据分析。
Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and size (usually body weight), but it can also involve brain weight for metabolized drug. Through all species, the protein binding of sumatriptan is similar (14-16%), and its metabolic pathway undergoes extensive oxidative deamination involving the monoamine oxidase A isoenzyme. These similarities across species suggested the possible relevance of an allometric analysis. Toxicokinetic data were collected from rats, pregnant rabbits, and dogs in animal pharmacokinetic studies where sumatriptan was administered intravenously to the animals at doses of 5 mg/kg, 0.25 mg/kg, and 1 mg/kg, respectively. Animal data were pooled and analyzed in one step using a mixed effect modeling (population) approach. The kinetic parameters predicted in any species were close to the observed values by species. 77 L/hr vs. 80 L/hr in man for total clearance, 137 L. vs. 119 L, for distribution volume at steady state. The value of the mix-ed effect modeling approach compared to the two-step method was demonstrated especially with the possibility of including covariates to describe the status of animal (e.g., pregnancy) in the model. Knowledge of the animal kinetics, dynamics, and metabolism of a drug contributes to optimal and expeditious development. Valuable information for the design of the first-dose-in-man study may expeditious more creative data analysis based on all the information collected during the preclinical and ongoing nonclinical evaluation of a new drug.