Background:
Mass balance studies conducted using radiolabeled material (14C or 3H) definitively
characterize the Absorption, Metabolism, and Excretion (AME) of a drug. A critical aspect of
these studies is that the radiotracer maintains its proportion to total drug from its administration to its
complete elimination from the body. In the study of GDC-0276 in beagle dogs, we observed that the
14C radiotracer proportion (specific activity) varied through the study.
Method:
High resolution-accurate mass spectrometric measurements of 12C and 14C isotopes of GDC-
0276 and its metabolites in plasma and excreta samples were used to determine the apparent specific
activities, which were higher than the specific activity of the dosing formulation. Drug concentrations
were adjusted to the observed specific activities to correct the readouts for GDC-0276 AME and PK.
Results:
The enrichment of 14C, which resulted in higher specific activities, was consistent with faster
and more extensive absorption of the radiotracer from the dosing formulation. This resulted in overestimating
the dose absorbed, the extent of elimination in urine and bile, and the exposures to circulating
metabolites. These biases were corrected by the specific activities determined for study samples by
mass spectrometry.
Conclusion:
Assuming that the radiotracer was proportional to total drug throughout a radiolabeled
study was not valid in a 14C study in beagle dogs. This presumably resulted from unequal absorption of
the radiotracer and nonradiolabeled test articles from the oral dose due to inequivalent solid forms. We
were able to provide a more accurate description of the AME of GDC-0276 in dogs by characterizing
the differential absorption of the radiotracer.
Mass Balance and Drug Interaction Potential of Intravenous Eravacycline Administered to Healthy Subjects
