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The rationale for early toxicology
One of the central problems in pharmaceutical
development is the selection of the most appropriate molecule to
develop in any indication. Whenever there is a choice, it is
important to balance all the properties of the molecular series so
that the best candidate is taken forward. A carefully selected
programme of experiments is likely to save a large amount of money
and precious development time later on and will make an early entry
to man or early trials much easier. In addition to characterisation
of physical-chemical
characteristics, such a programme should include comparative studies
in pharmacology and toxicology, which may include early ADME
(Absorption,
Distribution,
Metabolism and Excretion) evaluation. For any new chemical class,
this will also give an indication of any effects or properties that
are related to the class of chemical or its pharmacological target,
as distinct from those due to individual compounds. Furthermore,
this holistic approach facilitates the definitive evaluation of the
compound when it enters development, by helping choice of the
correct investigations.
 In
selecting a candidate drug for development from a large number of
molecules, it is usual to start with a programme of in vitro studies
that are designed to indicate pharmacological activity, absorption
potential and some early measures of toxicity in simple test
systems, which may include assessments of genomics and proteomics in
appropriate cell lines. However, when the list of candidates has
been reduced to less than 10 compounds, the test systems used should
be more complex in order to answer more general questions such as
"Is it toxic? " or "How does its toxicity compare with other
molecules in the same class of chemical?" and "Is it absorbed and,
if so, by how much?"
To answer these questions it is usually
necessary to perform some simple experiments in animals, often rats
or mice, that will give an indication of toxicological potency and
effect and, with appropriate blood sampling, an early indication of
absorption and pharmacokinetics. As these studies are conducted in
rodents, the amount of material needed can be small - depending on
the potency of the compounds under study.
Pipeline Biotech
specialises in the conduct of comparative studies
in which several compounds are administered to small numbers of rats
or mice and limited toxicological assessments are carried out. These
studies give an idea of relative toxicity and effect and facilitate
selection of one two candidates for further investigation. |
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