9.3.2 Tissue Distribution Study to Support the Human ADME Study
One of the key studies that the FDA and investigative review boards (IRB)
require the sponsors to do to support a human ADME protocol with
radiolabeled compound is to conduct tissue distribution studies in pigmented
animals, to provide dosimetry to various tissues and organs. The Long–Evans
rat, since they are pigmented, is the most common species used for this
purpose. Typically, these studies are limited to single dose by the intended
route of administration (PO, IV, SC, etc.). Various tissues are collected at
different time points and measured for radioactivity. The common techniques
used for counting radioactivity in tissues are (1) liquid scintillation counting
(LSC) of the tissue homogenate after appropriate processing or combustion of
the tissues to CO 2 that is trapped and counted for radioactivity and (2)
quantitative whole body autoradiography (QWBA), where thin sections of the
whole animals are prepared and then exposed to a phosphorimaging screen
that is then scanned with a phosphor imager. Figure 9.2 shows a typical
QWBA image of rat after administration of a C-14-labeled compound.
Readers are encouraged to refer to the review articles referenced here that
describes in detail the use of tissue distribution studies in the pharmaceutical
industry (Solon and Kraus, 2001; Solon et al., 2002). Based on body surface
area and body weight, exposure of radioactivity to the tissues in rat is
extrapolated to human tissues and used to estimate a whole body exposure
(WHO,1977). For most compounds, administration of a 100-mCi radioactive
single dose typically exposes the human subjects to an effective dose equivalent
of<20 mrem, well below the radiation limit set by the Nuclear Radiation
Committee of 3000 mrem (Hall, 1994; Valentin, 2002).
In addition to the tissue distribution study mentioned above for human
dosimetry, other tissue distribution studies, namely, maternal–fetal and milk
excretion studies are also conducted during the drug development process.
These studies are required for the registrational filing and are typically
conducted in rat species used in the toxicological evaluation. Data from
pregnant rat studies provide information about the drug’s potential to cross the
placental barrier and expose the fetus. Data from lactating animals provide
information about the drug’s potential to be excreted into the milk. Based on
the outcome of these studies, appropriate cautionary statements are made in
the product label for treating pregnant or lactating female patients.
9.3.3 Nonclinical and Clinical ADME Studies
ADME studies provide information on absorption, distribution, metabolism,
and excretion for the compound of interest in animals and humans. In drug
development, these studies are performed with either C-14- or tritium-labeled
material to provide detailed quantitative information on the circulating
metabolites, the extent of metabolism and routes of excretion for drug and
its metabolites. Readers are encouraged to refer Chapter 18 of this book for
more detailed discussion on ADME study design and data presentation.
268 ROLE OF DRUG METABOLISM IN DRUG DEVELOPMENT