动物和人类小分子消除和排泄的可预测性,及其对放射性标记药物人类ADME研究剂量学的影响。

IF 1.3 Q4 PHARMACOLOGY & PHARMACY
Ad Roffel, Jan Jaap van Lier, Gerk Rozema, Ewoud-Jan van Hoogdalem
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引用次数: 0

摘要

背景:我们评估了动物ADME研究中尿和粪便中14c标记药物的排泄对人类ADME研究的预测程度。我们将观察到的血浆消除半衰期与研究前预测的人体总药物相关放射性进行了比较,并估计了任何重大差异对人体剂量学计算的影响。方法:我们纳入了34项14C剂量大于0.1 MBq的人ADME研究。我们计算了剂量学输入参数的比率(人与动物的粪便排泄百分比;观察到的人体半衰期(与研究前预测的半衰期相比)和输出参数(研究后有效剂量与研究前有效剂量相比)并评估它们之间的关系。结果:定量相关性评估未显示整个数据集中粪便中排出的14C百分比与剂量学结果比率之间存在统计学显著相关性,但在评估基于ICRP 60/62的研究时发现具有统计学显著相关性(n=19项研究;P = 0.0028)。血浆半衰期比值与剂量测定结果比值之间也存在相关性。定量相关性评估显示,这些比值之间存在统计学上显著的相关性(结论:在发现人类血浆中14C的消除半衰期比预测值更长的所有情况下,辐射负担仍在ICRP IIa类范围内。将实际辐射负荷控制在1.00毫西弗限值以下似乎也部分取决于我们选择将14C剂量限制在3.7毫西弗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Predictability of Elimination and Excretion of Small Molecules in Animals and Humans, and its Impact on Dosimetry for human ADME Studies with Radiolabeled Drugs.

Background: We assessed the extent to which urinary and fecal excretion of 14C-labeled drug material in animal ADME studies was predictive of human ADME studies. We compared observed plasma elimination half-lives for total drug-related radioactivity in humans to pre-study predictions, and we estimated the impact of any major differences on human dosimetry calculations.

Methods: We included 34 human ADME studies with doses of 14C above 0.1 MBq. We calculated ratios of dosimetry input parameters (percentage fecal excretion in humans versus animals; observed half-life in humans versus predicted pre-study) and output parameters (effective dose post-study versus pre-study) and assessed their relationship.

Results: A quantitative correlation assessment did not show a statistically significant correlation between the ratios of percentages of 14C excreted in feces and the ratios of dosimetry outcomes in the entire dataset, but a statistically significant correlation was found when assessing the studies that were based on ICRP 60/62 (n=19 studies; P=0.0028). There also appeared to be a correlation between the plasma half-life ratios and the ratios of dosimetry results. A quantitative correlation assessment showed that there was a statistically significant correlation between these ratios (P<0.0001).

Conclusion: In all cases where the plasma elimination half-life for 14C in humans was found to be longer than the predicted value, the radiation burden was still within ICRP Category IIa. Containment of the actual radiation burden below the limit of 1.00 mSv appeared to be determined partly also by our choice to limit 14C doses to 3.7 MBq.

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来源期刊
CiteScore
4.80
自引率
9.10%
发文量
55
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