7.2.2 Use of Radiolabeled Materials
The FDA regulation of the use of radiolabeled drugs in drug development was
published in 21 CFR 361.1 Radioactive Drug for Certain Research Uses
(FDA, 2005a). It defines the objectives of the use of radioactive drugs in human
subjects to obtain basic information regarding metabolism, human physiology,
pathophysiology, and biochemistry, but not intended for immediate ther-
apeutic or diagnostic purposes or to determine the safety and effectiveness of
the drug. To ensure the safe and effective use of radioactive drugs, the
document requires that studies with a radiolabeled drug should be approved by
Radioactive Drug Research Committee. Doses used in these studies should not
exceed the dose limitations applicable to the separate administration of the
active ingredients with nonradiolabeled materials, and the recommended
maximal dose of radioactivity. Tissue distribution studies in rats can provide
the data to calculate dosimetry for the use of the radioactive drugs in human
subjects. The details of the rat tissue distribution study design and radioactivity
dosimetry calculation are described in Chapter 18.
7.2.3 Metabolite Safety Assessment
Traditionally, plasma concentrations of a parent drug have been used as an
index of systemic exposure to drug-related materials in animals and humans.
When drug blood or plasma concentrations in toxicological species are higher
than those in humans, it is assumed that potential clinical safety of the drug has
been appropriately evaluated during standard nonclinical toxicity studies.
However, in some cases, the toxicity of drugs is mediated by their metabolites.
Therefore, if a metabolite is present in humans but absent in toxicological
species or has higher exposure levels in humans than in the toxicological
species, the safety of the metabolite may not be adequately assessed in toxicity
studies with the animal models. To address the concern of metabolite safety
assessment, the FDA guidance ‘‘Carcinogenicity Study Protocol Submissions’’
(FDA, 2002) (Table 7.1) recommends that the following drug metabolism
information be included in the carcinogenicity study protocol:
(1) Metabolite profiles in humans and in the species employed in
carcinogenicity study. In cases where in vivo metabolism data are
unavailable,in vitrodata can be used.
(2) Toxicokinetic data that are sufficient to estimate steady state AUC
(0–24) for the drug and each major human metabolites at doses
employed in the range finding study.
(3) Exposure [steady state AUC (0–24) data] for the drug and major
metabolites in humans.Similar suggestions are also included in the ICH Guideline, ‘‘Dose Selection
for Carcinogenicity Studies of Pharmaceuticals’’ (ICH, 1995).
REGULATORY GUIDANCES RELEVANT TO DRUG METABOLISM 207