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Linking Pharmacovigilance with Pharmacogenetics

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Abstract

The ability to identify individuals who are susceptible to adverse drug reactions (ADRs) has the potential to reduce the personal and population costs of drug-related morbidity. Some individuals may show an increased susceptibility to certain ADRs through genetic polymorphisms that alter their responses to various drugs.

We wished to establish a methodology that would be acceptable to members of the general population and that would enable estimation of the risks that specific genetic factors confer on susceptibility to specific ADRs. Buccal swabs were selected as a minimally invasive method to obtain cells for DNA extraction. We wished to determine whether DNA of sufficient quantity and quality could be obtained to enable genotyping for two different polymorphic genes that code for enzymes that are widely involved in drug disposition.

This article describes a small pilot study of methodology developed in the New Zealand Intensive Medicines Monitoring Programme (IMMP) to link prescription event monitoring (PEM) studies with pharmacogenetics. The methodology involves a nested case-control study design to investigate whether patients with genetic variants in P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 are more susceptible to psychiatric or visual disturbances following cyclooxygenase-2 inhibitor use (ADR signals identified in the IMMP database) than matched control patients taking the medication without experiencing any ADRs.

It was concluded that the use of buccal swabs is acceptable to patients and provides DNA of sufficient quantity and quality for genotyping. Although no differences in the distribution of genotypes in the case and control populations were found in this small study, case-control studies investigating genetic risks for ADRs using drug cohorts from PEM studies are possible, and there are several areas where population-based studies of genetic risk factors for ADRs are needed.

Examples are discussed where research in large populations is required urgently. These are: (i) genetic variations affecting P-gp function; (ii) variations affecting drugs metabolised by CYP2C9 and other polymorphic CYP enzymes; (iii) genetic variation in β-adrenergic receptors and adverse outcomes from β-adrenoceptor agonist therapy; and (iv) genetic variation in cardiac cell membrane potassium channels and their association with long QT syndromes and serious cardiac dysrhythmias.

Such studies will help to identify factors that increase the risk of unwanted outcomes from drug therapy. They will also help to establish in what circumstances genotyping should be performed prior to commencing drug treatment and in tailoring drug treatment for individual patients.

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Acknowledgements

A generous grant from the New Zealand Pharmacy Education and Research Foundation has enabled us to undertake the experimental work described in this article. We are also grateful to Janelle Ashton for invaluable assistance with this study and to Deborah Layton and Andrew Boshier for further information on pharmacogenetic studies initiated in the Drug Safety Research Unit. Dr Kennedy is a Senior Research Fellow of the Health Research Council of New Zealand. Dr Roberts is the recipient of a Health Sciences Career Development Award of the University of Otago. The New Zealand Intensive Medicines Monitoring Programme (IMMP) has been supported financially by Medsafe of the NZ Ministry of Health and some pharmaceutical companies, in particular, Merck Research Laboratories, USA.

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Authors and Affiliations

  1. The New Zealand Intensive Medicines Monitoring Programme (IMMP), New Zealand Pharmacovigilance Centre, Department of Preventive and Social Medicine, Otago Medical School, NZ Pharmacovigilance Group Dunedin School of Medicine, P.O. Box 913, Dunedin, New Zealand

    David W. J. Clark & David M. Coulter

  2. Department of Pharmacology and Toxicology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand

    David W. J. Clark & Emma Donnelly

  3. University of Otago, Gene Structure and Function Laboratory, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand

    Rebecca L. Roberts & Martin A. Kennedy

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  1. David W. J. Clark
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  2. Emma Donnelly
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  3. David M. Coulter
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  4. Rebecca L. Roberts
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  5. Martin A. Kennedy
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Correspondence to David W. J. Clark.

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Clark, D.W.J., Donnelly, E., Coulter, D.M. et al. Linking Pharmacovigilance with Pharmacogenetics. Drug-Safety 27, 1171–1184 (2004). https://doi.org/10.2165/00002018-200427150-00002

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