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Abstract: New drug development is a long, complex
and expensive activity. Surveys over the past 10 years
have shown that whereas R & D expenditure is increasing
almost exponentially, the number of new drugs being
introduced in market is either static or declining.
Evaluating the safety and efficacy of a successful human
medicine involves many animal studies, which can
sometimes be subjected to considerable suffering and
distress. Safety, efficacy and toxicology failures are
responsible for failures in drug development. Another
important reason for drug failures in the development
phases is suboptimal pharmacokinetics. Efficacy failure
could either result due to low concentration of drug at
the target site in the body or drug reaching the target
in an inappropriate amount of time. Safety failures may
be due to the wrong concentration reaching the wrong
target for too long a time period. Toxicity failures in
animal studies may be due to metabolic processes or
pathways that do not occur in humans. It is very
important to understand the pharmacokinetic profile of a
new chemical entity (NCE) in its early stage of
development to determine whether NCE can be transformed
into a drug or not. Animal studies and in vitro methods
are conventionally used for studying drug metabolism
pathways prior to human studies. Also, it is necessary
to extrapolate data on pharmacokinetics from in vitro
and animal studies to humans. However, it is not always
necessary that a candidate drug would show the same
response in humans as it showed in animal models. While
using candidate drug in humans for the first time, there
is always a concern that pharmacokinetic profile might
be different from the animal studies.
Phase 0 Studies
The phase 0 or microdosing or exploratory
investigational new drug (IND) studies are done for
obtaining clinical information on a newly discovered
molecule in the early clinical developmental phase.
During pharmaceutical development, large numbers of
molecules are generated with the goal of identifying the
most promising candidates for further development. These
molecules are generally structurally related, but can
differ in several ways. Promising candidates are often
selected using in vitro testing models that examine
binding to receptors, effects on enzyme activities,
toxic effects, or other in vitro pharmacologic
techniques. Candidates that are not rejected during
these early tests proceed to in vivo animal testing for
efficacy and safety. Commonly, a single candidate is
selected for an IND application and introduction into
human subjects, initially healthy volunteers in most
cases.
The microdosing studies help in identifying the best
candidates for further development and eliminate those
which do not hold promise. These studies are done at
very early stage of Phase 1 clinical trial and involve
very limited human exposure which have no therapeutic or
diagnostic intent. Microdosing is a method for studying
the in vivo behaviour of INDs through administration of
doses so small that they are unlikely to produce
whole-body effects, but large enough to elicit the
cellular response to be studied. Thus, it is possible to
see the pharmacokinetic profile of the IND with almost
no risk of adverse effects. It is usually done before
testing on animals to predict whether a drug is viable
for the next phase of testing. This allows only best
drug candidates to advance further, which is more
expensive and extensive clinical development.
Microdosing studies are conducted prior to the
traditional dose escalation, safety, and tolerance
studies and provide vital information on
pharmacokinetics and bioavailability of a prospective
drug.
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