today that have produced some type of positive
response in these studies, and yet it has been
concluded that no human risk is present or the
potential risk is not known (e.g. aspirin causes
chromosomal breaks). Mutagenicity studies in
drug development are rarely published: either
the studies are negative and uninteresting to jour-
nal editors, or they are positive and the drug fails
to survive the development process. However, a
fairly standard worked example is provided by
Foxet al. (1996).
Pharmacokinetic studies
In the early stages of drug development, it is impor-
tant to identify important parameters that relate to
the absorption and excretion pathways for the drug.
In the later stages of development, studies on the
extent of tissue distribution and the identification
of metabolites become important. Another reason
why this is important is that it assists the investi-
gator in knowing that the appropriate species has
been selected for the nonclinical toxicology pro-
gram. It is important to human safety evaluation
that the nonclinical models chosen are representa-
tive of the metabolism of the drug in humans.
Therefore, it is necessary to have pharmacokinetic
information early in the program, so that it can be
compared to the data generated in the early clinical
studies.
Drug metabolism is a highly specialized field
and is increasing in sophistication all the time. A
relatively new technique that is available to the
preclinical investigator is the use ofin vitrometh-
ods to establish and confirm similar mechanisms in
drug metabolism between animals and humans
(see Chapter 10). These procedures involve the
use of liver slices and/or liver hepatocyte homo-
genates and can be done in human and animal
cultures at the earliest stages of drug development.
Toxicokinetic data are generally obtained from
repeated-dose toxicity studies and generally deter-
mine whether (a) the plasma concentrations of the
drug increase in a linear fashion over the range of
the increasing doses used in the studies; (b) plasma
concentrations increase over time, suggesting an
accumulation of the drug in plasma or tissues;
(c) there is a relationship between the plasma con-
centrations of the drug (or metabolites) and the
toxicity associated with higher levels of the drug;
and (d) the effects are more closely related to peak
concentrations or to overall exposure (measured by
the area under the concentration time curve, AUC).
Toxicokinetic data are generally collected on the
first day of dosingin a repeated-dose study and near
the last day of dosing, that is during the last week,
of a 90-day toxicity study. In rodent studies, satel-
lite groups of animals are required due to the blood
volumes needed for assay. For larger non-rodents,
the main study animals can usually provide the
samples. Guidelines have been made available
that cover most aspects of collection and analysis
of these data (Federal Register, 1 March 1995).
Lastly, pharmacokinetic assessment requires
tissue distribution studies in nonclinical models
to determine the extent of localization of the drug
in tissues. In some situations, where single-dose
tissue distribution studies suggest drug localiza-
tion, a tissue distribution study following repeated
dosing may be indicated. The conditions under
which such studies may be necessary have been
delineated in an ICH guideline (Federal Register,
1 March 1997).Safety pharmacology
Studies related to safety pharmacology (sometimes
confusingly termed‘general pharmacology’studies)
tend now to be performed earlier in the drug devel-
opment process than was previously the case.
Although in some respects considered an aspect of
the disciplineof pharmacology,thepurpose of safety
pharmacology is to evaluate the potential pharma-
cological properties that may be unrelated to the
intended indication for the drug. An example of
this would be significant effects of a drug on the
cardiovascular system that may actually be under
development for the treatment of gastric ulcers. In
such a case, there is a specific guidance for examin-
ing in animals the potential for a test substance to
cause changes in hemodynamics and QT prolonga-
tion on the ECG.
Most major developed countries have stated
guidelines indicating that safety pharmacology6.6 TOXICOLOGICAL SUPPORT PRE-IND AND FOR PHASE I CLINICAL STUDIES 69