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
Volume: 17
Issue: 1
Author(s): Ad Roffel*, Jan Jaap van Lier, Gerk Rozema and Ewoud-Jan van Hoogdalem
Affiliation:
- Department of Scientific Affairs, Clinical Pharmacology, PRA Health Sciences, Groningen, The Netherlands
Keywords:
Dosimetry, ADME, excretion, 14C, ICRP, effective dose.
Abstract: 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.
