Abstract
During preclinical and early phase clinical studies of drug candidates, exposure to metabolites should be monitored to determine whether safety conclusions drawn from studies in animals can be extrapolated to humans. Metabolites accounting for more than 10% of total exposure to drug-related material (DRM) in humans are of regulatory concern, and for any such metabolites, adequate exposure should be demonstrated in animals before large-scale phase 3 clinical trials are conducted. We have previously identified six metabolites, M1–M6, of the gastroesophageal reflux inhibitor lesogaberan. In this study, we measured exposure in humans, rats, and beagle dogs to lesogaberan and these metabolites. Plasma samples were taken at various time points after lesogaberan dosing in two clinical and three preclinical studies. Concentrations of lesogaberan and its metabolites were measured, and exposures during a single dosing interval were calculated. The parent compound and metabolites M1, M2, M4, and M5 were together shown to constitute all significant exposure to DRM in humans. Only M4 and M5 were present at levels of regulatory concern (10.6% and 18.9% of total exposure to DRM, respectively, at steady state). Absolute exposure to M5 was greater in rats during toxicology studies than the highest absolute exposure observed in humans at steady state (117.0 µmol × h/liter vs. 52.2 µmol × h/liter). In contrast, exposure to M4 in rats was less than 50% of the highest absolute exposure observed in humans. Further safety testing of this metabolite may therefore be required.
Footnotes
- Received December 20, 2013.
- Accepted March 21, 2014.
The study was funded by AstraZeneca R&D, Mölndal, Sweden.
Ann Aurell Holmberg, Anja Ekdahl and Lars Weidolf are employees of AstraZeneca R&D, Mölndal, Sweden.
Presented as a poster at the International Society for the Study of Xenobiotics (ISSX) annual meeting, Holmberg A, 29 September-3 October 2013, Toronto, ON, Canada. Abstract published in ISSX Online Abstracts, Supplement 8, No. 2, 2013 (http://issx.confex.com/issx/intl10/webprogrampreliminary/Paper29458.html).
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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