pharmacological screening to general pharmacol-
ogy and toxicology, all with pharmacokinetic sup-
port, which involves the development of
pharmacokinetic and pharmacodynamic models.
As a chemical series develops, correlations such
as that in Figure 8.6 are developed. Eventually, a
compound or compounds is/are chosen for phase I
studies.
In this scheme, phase I is influenced by pharma-
cokinetic and pharmacodynamic modeling. This
modeling is used to refine the phase I protocol,
providing advice on sampling times, doses and
warning signs of difficulty if they occur, as well
as permitting comparison of, for example, EC 50
data from humans with EC 50 data from animals and
in vitro/in vivocomparisons. The objective is expe-
ditious choice of the best compound, with the ever-
present limitations on information available. Note
that this scheme can involve feedback from phase I
to renewed chemical synthesis, as well as choice of
a second or third compound for human testing.
Currently, phase I studies themselves tend to be
quite straightforward and focus on single com-
pounds. Typically, after adequate preclinical char-
acterization of a candidate drug and 14-day and/or
3-month multiple-dose toxicology studies in two
mammalian species, a very low dose is chosen for
the first human exposure to the drug. In later expo-
sures, the dose is escalated according to some pre-
arranged criteria until the drug concentrations in
plasma associated with undesirable properties in
animals are reached and/or until some other limiting
response is threatened or observed in the human
volunteers. Doses may be single or short multiple-
dose series. Simple physiological and biochemical
measurements are routinely made in order to moni-
tor for safety. If possible, responses to the drug are
also measured when relevant to the intended ther-
apeuticuse.AdrugsuccessfullypassestophaseIIif,
with appropriate plasma levels, responses are pre-
dictable, reversible, related to the known pharma-
cological mechanisms of the drug and there is a
viewpoint among the investigators concerned that
the drug could safely be given in initial studies to
patients from its target population. Hopefully, all or
most of what is observed in phase I is in line with
predictions based on the pharmacokinetic and phar-
macodynamic properties of the drug in animals.
Once phase I is complete, the humans become
the first-choice test species, under all but the most
specialized of circumstances (e.g. effects on repro-
duction). In this context, phase I serves as the
interface between preclinical research and clinical
development, and the validity of the predictions
from animals to humans involved is of paramount
importance.
We believe that with enhanced integrated study
of animals and humans and with data feedback
based on computer models, the process of drug
discovery from synthesis to proof of safety in
humans could be dramatically improved in its
efficiency. This is beyond what has traditionally
been expected from departments of drug metabo-
lism and pharmacokinetics (Welling and Tse,
1995). The time saved could be used to permit a
larger number of compounds with better pro-
spects, from a single research program, to be
compared in phase I studies. Consequently, the
extremely costly testing programs in patients
which follow phase I could be started sooner and
conducted better.
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98 CH8 PHASE I: THE FIRST OPPORTUNITY FOR EXTRAPOLATION FROM ANIMAL DATA