Making
use of pharmacogenetic knowledge depends upon; a) understanding
the relative significance of genetic vs. other sources of variation
(environmental, physiological and pathological) and b) the ability
to correlate genotype with clinical response.
Pharmacogenetic
tests have been used retrospectively to explain unusual responses
and in prospective studies involving small panels of
pre-genotyped subjects. We are observing currently an increase
in demand for preselecting patients for clinical trials on the
basis of phase I or phase II enzyme polymorphisms, particularly
in the case of phase I clinical trials.
In
phase II clinical trials case control studies should be adequate
although, in our opinion, prospective randomised genotyping assays
are preferable. In phase II and IV clinical trials, then double
blind randomised controlled trials should be performed.
The
consequences of not understanding metabolic variability in clinical
trials can be considerable:
- Drugs
may fail late in clinical development
- Iatrogenic
disease may occur, i.e. there may be drug associated morbidity
and mortality
- There
may be restrictions placed on drug use
- A drug
may be withdrawn from the market
Variation
in pharmacokinetics, predominantly due to genetic polymorphisms
in the drug metabolising enzymes is responsible for part of this
metabolic variation. That the metabolism of a drug is determined
by enzymes which exhibit polymorphism is not a priori a reason
to curtail its development despite there perhaps being substantial
pharmacokinetic variability.
As
with many biological systems there is redundancy in the drug metabolism
enzyme system. The successes to date have to some extent been
based on large effects such as those revealed by CYP2D6 genotype
profiles. Most drugs however, are cleared by multiple pathways,
i.e. are not metabolised solely by a single enzyme. We consider
that the study of polygenic polymorphisms in the drug metabolising
enzymes will become of increasing importance.
Please
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