8 Phase I: The First Opportunity

for Extrapolation From Animal

Data to Human Exposure

Stephen H. Curry, Dennis McCarthy, Helen H. DeCory, Matthew Marler

andJohan Gabrielsson

Successful preclinical drug discovery programs
frequently reach a point where there is a need to
choose one or two candidates from among a whole
pharmacological class of new drugs for phase I
testing (Welling and Tse, 1995). There is thus a
crucial need to make reliable and rapid predictions
of human responses from animal data.
Although drug discovery is primarily designed
to find compounds with desired efficacy, the choice
from among multiple compounds potentially offer-
ing efficacy often comes down to those with the
most favorable pharmacokinetics (Welling and
Tse, 1995). Thus, compounds are chosen using
animal data, partly because of suitable bioavail-
ability, half-life and tissue penetration character-
istics. As we shall discuss below, the possibility of
multiphasic plasma level decay patterns following
intravenous dosing is an important element in this
selection process.
Pharmacokinetics, related when possible to the
observed drug effects, is a powerful and critical
component of the pivotal step from animal research
to human research in the drug development pro-
cess. Data for chosen compounds will commonly
also have been subjected to simultaneous modeling
of pharmacokinetic and pharmacodynamic data
from animals, again in an effort to optimize the
chances that the drugs chosen will have the proper-

ties in humans specified in a prediscovery product

profile. Meanwhile, the pharmacodynamic infor-

mation available typically includes data from

receptor-binding studies,in vitrofunctional assays

andin vivo pharmacological screening experi-

ments. The essence of this crucial step of drug

development, taking the new drug into human

beings, is the making of valid predictions of

in vivodrug effects fromin vitrodata.

The collection ofin vitrodata from animal mate-

rials and extrapolation (a) from physical properties

toin vitrodata, (b) fromin vitrodata to nonhuman

in vivodata, and (c) from nonhumanin vivodata to

clinicalin vivoresponses can be done more effi-

ciently using online analysis and simulations. This

chapter seeks to show how rapid progression may

be achieved for new chemical entities through this

process, using in vitro and in vivo data and

advanced modeling procedures. This must be

seen in the context of the entire drug discovery

process, which, on a larger scale, is designed to

find potent, safe drugs (in humans), based on ani-

mal data (Figure 8.1). We anticipate a time whenin

vitro pharmacodynamic data will be routinely

combined within vitrodrug metabolism data in a

rational prediction of drug responses in healthy

human volunteers, with consequent acceleration

of the drug discovery effort, and therefore a general

Principles and Practice of Pharmaceutical Medicine, 2nd Edition Edited by L. D. Edwards, A. J. Fletcher, A. W. Fox and P. D. Stonier
#2007 John Wiley & Sons, Ltd ISBN: 978-0-470-09313-9