Chapter category: Pharmacogenomics
Pharmacogenetics, Ethnic Differences in Drug Response and Drug Regulation
Pharmacogenomics
in Admixed Populations
Edited by: Guilherme Suarez-KurtzISBN: 978-1-58706-311-4
» Get more information about this book at landesbioscience.com «
Chapter authors:
Rashmi R. Shah
The two key components in the pathway between the administration of a drug and the clinical response it elicits are the dose-concentration (pharmacokinetic) and/or concentration-response (pharmacodynamic) relationships of the drug. Both these components are subject to genetic influences that account for a substantial fraction of inter-individual variability in drug response. Arising from inter-ethnic differences in the frequency of the variant alleles that exert these genetic influences, it is intuitive to anticipate inter-ethnic differences in pharmacokinetics, pharmacodynamics and dose-response relationships of a drug. These frequently translate into differences in drug response. For a variety of reasons, these differences have not hitherto been investigated systematically. The problem is further compounded by difficulty in characterizing ethnicity because of ethnic admixture. This admixing exaggerates any dissociation of genes that determine drug response from those that determine skin color and other anthropological features. Nevertheless, there are examples of significant inter-ethnic differences in drug response as illustrated by ibufenac, clioquinol and gefitinib. Increasingly, drug development programs are undertaken at a global level with the aims of reducing costs, expediting the development process and addressing issues arising from global prescribing of drugs. Drug regulatory authorities have responded to these challenges by promulgating a number of guidelines that recommend sponsors of new drugs to explore the role of genetic variations in differences in drug response between individuals and between ethnic populations. When inter-ethnic differences are anticipated, bridging studies may be required before data from one ethnic population can be extrapolated to another. The nature of bridging studies is determined on a case-by-case basis and may include (i) pharmacokinetic studies, (ii) pharmacodynamic studies, (iii) dose-response studies and/or (iv) pivotal Phase III studies for either safety and/or efficacy. The recent approval by the US FDA of ‘BiDil’ for the treatment of cardiac failure in self- identified black patients is a spectacular verification of the regulatory desire to address ethnicity-related issues. Furthermore, regulatory determination for promoting safe and effective prescribing of drugs and improving pharmacovigilance at a global level without compromising efficient drug development requires the sponsors to discuss proactively the target populations that have not been adequately studied during the preapproval period. These include sub-populations carrying known and relevant genetic polymorphism and patients of different racial and/or ethnic origins. Regulatory authorities may refuse to accept an application when issues arising from ethnicity are not adequately addressed. With increasing global migration and the resulting admixing of different ethnic populations, the challenges in the future will be even greater.
Rashmi R. Shah
Rashmi Shah Pharmaceutical Services,
Gerrards Cross, Bucks, United Kingdom
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