Ad Roffel, Jan Jaap van Lier, Gerk Rozema, Ewoud-Jan van Hoogdalem
{"title":"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。","authors":"Ad Roffel, Jan Jaap van Lier, Gerk Rozema, Ewoud-Jan van Hoogdalem","doi":"10.2174/1574884716666210309103625","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>We assessed the extent to which urinary and fecal excretion of <i>14</i>C-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.</p><p><strong>Methods: </strong>We included 34 human ADME studies with doses of <i>14</i>C above 0.1 MBq. We calculated ratios of dosimetry input parameters (percentage fecal excretion in humans <i>versus</i> animals; observed half-life in humans <i>versus</i> predicted pre-study) and output parameters (effective dose post-study <i>versus</i> pre-study) and assessed their relationship.</p><p><strong>Results: </strong>A quantitative correlation assessment did not show a statistically significant correlation between the ratios of percentages of <i>14</i>C 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).</p><p><strong>Conclusion: </strong>In all cases where the plasma elimination half-life for <i>14</i>C 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 <i>14</i>C doses to 3.7 MBq.</p>","PeriodicalId":29871,"journal":{"name":"Current Reviews in Clinical and Experimental Pharmacology","volume":"17 1","pages":"26-38"},"PeriodicalIF":1.3000,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Predictability of Elimination and Excretion of Small Molecules in Animals and Humans, and its Impact on Dosimetry for human ADME Studies with Radiolabeled Drugs.\",\"authors\":\"Ad Roffel, Jan Jaap van Lier, Gerk Rozema, Ewoud-Jan van Hoogdalem\",\"doi\":\"10.2174/1574884716666210309103625\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>We assessed the extent to which urinary and fecal excretion of <i>14</i>C-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.</p><p><strong>Methods: </strong>We included 34 human ADME studies with doses of <i>14</i>C above 0.1 MBq. We calculated ratios of dosimetry input parameters (percentage fecal excretion in humans <i>versus</i> animals; observed half-life in humans <i>versus</i> predicted pre-study) and output parameters (effective dose post-study <i>versus</i> pre-study) and assessed their relationship.</p><p><strong>Results: </strong>A quantitative correlation assessment did not show a statistically significant correlation between the ratios of percentages of <i>14</i>C 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).</p><p><strong>Conclusion: </strong>In all cases where the plasma elimination half-life for <i>14</i>C 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 <i>14</i>C doses to 3.7 MBq.</p>\",\"PeriodicalId\":29871,\"journal\":{\"name\":\"Current Reviews in Clinical and Experimental Pharmacology\",\"volume\":\"17 1\",\"pages\":\"26-38\"},\"PeriodicalIF\":1.3000,\"publicationDate\":\"2022-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current Reviews in Clinical and Experimental Pharmacology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2174/1574884716666210309103625\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Reviews in Clinical and Experimental Pharmacology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/1574884716666210309103625","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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.