Summary report from the Pharmacogenetics Working Party Inaugural Meeting, 25 January 2000
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INTERNATIONAL JOURNAL OF PHARMACEUTICAL MEDICINE 2000,14:121-122
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SOCiETy of PI-JARMACEUTicAl Mrdicivs Society Executive Secretary: Ms Amy Scales 20-22 Queensbury Place, London SW7 2DZ
Editor: Martin W. Lunnon
Summary report from the Pharmacogenetics Working Party Inaugural Meeting, 25 January
2000 Introductions - John PincoU (Chairman of the SPM) This working party would build on the success of previous working parties (e.g. drugs for asthma, anti-infective agents) and was also helped by the multi disciplinary nature of the Society.
Stephen Holgate (Working Party Chairman) The background into which the working party will be coming: • sequencing of the human genome will be completed in two to three years • human diseases are heterogeneous with respect to mechanism and response to treatment • currently there is tension between evidenced-based medicine which looks at total populations as opposed to approaches which are targeted at identifying specific groups patients • good drugs being rejected on the basis of rare side effects • a new style of co-operation which will be needed between academic, clinical industry researchers in order that the full expectations of sequencing the human genome can be realised).
Regulatory viewpoint (Rashmi Shah) From a regulatory perspective, it has long been appreciated that genetic factors can profoundly influence either the pharmacokinetics or the pharmacodynamics of a drug. Since the characterisation of genetic polymorphism in acetylation in 1960 and its implications for therapy with isoniazid and a few other drugs, many such polymorphisms have been described with regard to other important drug metabolising enzymes or the targets of drug action (receptors, channels, enzymes, etc.). Among the drug metabolising enzymes, the best characterised genetic polymorphism is that of CYP2D6. This cytochrome P450 isoform is responsible for the bio-
transformation of a wide range of cardiovascular and psychotropic drugs with narrow therapeutic index and intended for long-term administration. Not surprisingly, a 'standard' doseresponse curve may be applicable to the majority but not all of the population. The result is that following a 'standard' dose, a significant subset of the population is likely to develop concentration-related toxic response or fail to respond beneficially as expected. It is a sobering fact that a number of drugs have been withdrawn from the market directly as a result of this genetic variability in response. Perhexiline and phenformin are good examples but others such as terodiline and prenylamine are also likely to have been casualties of pharmacogenetics and failure to manage variability. With drug interactions, silent mutations of potassium channels are likely to have conspired in the withdrawals of terfenadine, astemizole and from July this year, cisapride from many markets. Recent advances in genetics have made it possible to identify the individuals with these variant traits and have raised the expectations of individualised drug therapy. From a regulatory po
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