Associating Genes to Drug Response
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W)2-8615/2002 Copyright 8 2002 Drug Informalion Association Inc.
ASSOCIATING GENES TO DRUG RESPONSE DAVIDA. KATZ, PHD Research Investigator Pharmacogenetics, Abbott Laboratories, Abbott Park, Illinois
Drug developers’ principal interest in pharmacogenetics is to learn which genes are releinant to variation in response to their drugs. Phannacogeneticists must overcome several inferential challenges to meet this need. False positive results can be avoided through experiment replication. Using the human genome as the ultimate measure of intrinsic differences between individuals, it can be demonstrated that results are not artifacts of population structure. Association analysis based upon estimated haplotypes is more powerful than single-marker methods to minimize the hazard of false negative results. This article summarizes the current state-of-the-art in pharmacogenetic inference and identifies areas .for further method development nork to enable identification of the genes underlying the efficacy or safety of a particular drug. Key Words: Pharmacogenetics; Drug development; Study design; Population structure;
Haplotypes
INTRODUCTION
offers one means to accomplish these ends, by identifying the intrinsic (ie, genetic) facSUBSTANTIAL VARIATION OF response tors leading to different responses in different between individuals is well known in clinical people. trials of drugs. Variable efficacy in the trial Numerous clinical observations of inherpopulation and the appearance of adverse ited differences in drug response have been events in a small number of individuals have described. The genes involved fall into three each frequently led to failure to gain regulabroad sets of biochemical pathways: pharmatory approval for compounds. Recently, regu- cokinetic, pharmacological, and physiological. latory authorities have revoked approval of Pharmacokinetic pathways are those involved several drugs owing to rare occurrences of in drug absorption, distribution, metabolism, toxicity. Given the substantial investment and excretion, mainly including genes encodmade to develop a drug and the large eco- ing drug metabolism enzymes and drug transnomic value of a successful drug, there is porters. Pharmacological pathways consist of considerable interest in understanding and the target(s) of a drug and proximal gene prodlimiting the variability of efficacy and safety ucts, such as proteins that physically interact during registration clinical trials, and once with a target or control its expression. Physidrugs are on the market. Pharmacogenetics ological pathways are those involved in maintaining homeostasis, such as the blood clotting cascade, as well as those involved in the Presented at the DIA “3rd Annual Workshop on Phar- etiology of diseases, such as apolipoproteins macogenetics,” November 19-20. 2001, Lisbon, Porin cardiovascular disorders. Genes in each of tugal. these classes have been associated with both Reprint address: David A. Katz, PhD, Abbott Laboefficacy and safety of dru
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