An evaluation of human ADME and mass balance studies using regular or low doses of radiocarbon.

Autor: Roffel AF; PRA Health Sciences, Groningen, The Netherlands., van Marle SP; PRA Health Sciences, Groningen, The Netherlands., van Lier JJ; PRA Health Sciences, Groningen, The Netherlands., Hartstra J; PRA Health Sciences, Groningen, The Netherlands., van Hoogdalem EJ; PRA Health Sciences, Groningen, The Netherlands.
Jazyk: angličtina
Zdroj: Journal of labelled compounds & radiopharmaceuticals [J Labelled Comp Radiopharm] 2016 Dec; Vol. 59 (14), pp. 619-626.
DOI: 10.1002/jlcr.3473
Abstrakt: There has been increased interest in conducting human absorption, distribution, metabolism, and excretion (ADME) studies with low doses (up to 0.1 MBq) as opposed to regular doses (1.85-3.7 MBq) of radiocarbon ( 14 C). This is due to the fact that low-dose human ADME studies may be conducted without dosimetry calculations and will lead to lower human radiation exposure. Here, we sought to compare the outcomes of low-dose versus regular-dose human ADME studies in healthy volunteers. Forty oral human ADME studies conducted at PRA were surveyed, among which 12 were low-dose studies. The fraction of drug material absorbed was 67% ± 7% in the regular-dose studies (data for 13 studies) versus 39% ± 16% in the low-dose studies (data for 5 studies). The average total recovery of 14 C in excreta was 93% ± 5% for regular-dose studies, and 21 of 28 such studies showed recoveries more than 90%. For low-dose studies, average total recovery was 89% ± 9%, and 6 of 12 studies showed recoveries more than 90%. Metabolite profiling was successful in all cases reported (13 regular-dose studies and 5 low-dose studies). There was no obvious relationship between the total recoveries of 14 C in excreta and the proportion of 14 C excreted in feces, or between the total recoveries and the plasma elimination half-lives for parent or total 14 C, neither in the low-dose nor the regular-dose studies. A significant correlation was found between the fraction absorbed and the recovery in feces in the low-dose but not in the regular-dose studies, and no correlation was found between the fractions absorbed and the total recoveries in both types of studies. Low-dose studies were more often conducted on drugs that had a plasma elimination half-life of parent drug more than 100 hours (5 of 12 studies) than regular-dose studies (1 of 26 studies). We conclude that both low-dose as well as regular-dose human ADME studies provide adequate data to support decision making for further drug development.
(Copyright © 2016 John Wiley & Sons, Ltd.)
Databáze: MEDLINE
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