trials, the staging of the studies that support clinical development and long-
term toxicology studies will be discussed here.
One major goal for conducting metabolism-related studies in both
nonclinical and human subjects is to make sure that the metabolites detected
in human circulation show exposure in the toxicology species. Therefore,
metabolism studies are conducted both in humans and in the toxicology species
used in the long-term safety studies. Prior to IND filing, in the absence ofin
vivohuman data,in vitrosystems like human liver microsomes and hepatocytes
are heavily relied on to get an early read on the potential human metabolites.
These studies along within vitroandin vivoanimal studies provide a qualitative
comparison of metabolism across species.
The timing of ADME studies in animals and humans, which are typically
conducted with radiolabeled material, depends on the drug development
strategy. Given the regulatory climate, and thatin vivodata are preferred (see
FDA and ICH guidelines) overin vitrodata, the current strategy employed in
much of the pharmaceutical industry is to do detailed ADME studies much
earlier during the lifetime of drug’s development. Often these studies are done
during the preclinical development to Phase 1 timeframe. The main objectives
of these studies are to answer the following questions: What is the major route
of elimination (urinary or biliary) in animals and humans? Will renal or hepatic
impairment affect the drug’s clearance? Does metabolism play a significant role
prior to elimination and, if so, what are the primary pathways of metabolism?
What are major metabolites in human plasma? Are major drug–drug
interaction anticipated? Will polymorphisms have a significant effect on
clearance? Are the toxicology species exposed to human metabolites? and
finally, will metabolites contribute to the pharmacological effects?
Data generated from the ADME studies could trigger more studies like
detailed reaction phenotyping studies to identify the enzymes involved in the
primary pathways of metabolism that in turn can guide some key clinical
interaction studies. Furthermore, the comparative data generated from the
ADME studies get incorporated into the carcinogenicity protocol to guide in
the dose selection for these studies. Decisions about monitoring for major
circulating metabolites, as per the MIST and FDA (draft) guidelines, can also
be made and appropriate assays developed for measuring the metabolites in the
upcoming studies.
9.3 IN VIVOADME STUDIES
The following section will focus on the detailed ADME studies conducted
during the drug development process to help understand the disposition of a
drug in nonclinical species and in humans. Since these studies are typically
conducted with radiolabeled compound, a short section on the use of
radiolabeled compound is included here along with a section on tissue
distribution studies conducted to support the human ADME study.
266 ROLE OF DRUG METABOLISM IN DRUG DEVELOPMENT