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:

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.

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