Correspondence
Pharmacogenetics
N Engl J Med 2003; 348:2041-2043May 15, 2003
- Article
To the Editor:
The review by Weinshilboum on the inheritance of drug response (Feb. 6 issue)1 focuses on the pharmacogenetics of drug metabolism as an important factor in the variability of drug effects among persons. An aspect of this topic that is not often addressed is the variability among patients (representing the majority) who carry wild-type alleles responsible for metabolizing enzymes. Responses to two drugs exemplify this variability. According to a recent study,2 metabolic clearance of warfarin in patients who are homozygous for the wild-type CYP2C9 allele ranges from about 130 ml per minute to 1500 ml per minute. The same applies to fluorouracil, an antineoplastic agent metabolized by the polymorphic enzyme dihydropyrimidine dehydrogenase, which exhibits remarkable variability in plasma clearance even among patients without an inherited deficiency of dihydropyrimidine dehydrogenase,3 because of dose- and time-dependent pharmacokinetics.4 These two examples do not diminish the importance of genetic factors, but they do indicate that acquired and environmental factors may be equally or even more important in explaining variability in the effects of drugs.
4 ReferencesRoberto Padrini, M.D.
Mariano Ferrari, M.D.
University of Padua, 35131 Padua, Italy
roberto.padrini@unipd. it 1
Weinshilboum R . Inheritance and drug response. N Engl J Med 2003;348:529-537
Full Text | Web of Science | Medline2
Scordo MG ,Pengo V ,Spina E ,Dahl ML ,Gusella M ,Padrini R . Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002;72:702-710
CrossRef | Web of Science | Medline3
Gusella M ,Toso S ,Ferrazzi E ,Ferrari M ,Padrini R . Relationships between body composition parameters and fluorouracil pharmacokinetics. Br J Clin Pharmacol 2002;54:131-139
CrossRef | Web of Science | Medline4
Terret C ,Erdociain E ,Guimbaud R , et al. Dose and time dependencies of 5-fluorouracil pharmacokinetics. Clin Pharmacol Ther 2000;68:270-279
CrossRef | Web of Science | Medline
To the Editor:
The articles on pharmacogenomics by Weinshilboum1 and by Evans and McLeod2 and the accompanying editorial by Goldstein3 fail to mention sex as a major genetic difference affecting pharmacokinetics and pharmacodynamics. There is considerable research on the effects of sex differences on the pharmacokinetics and pharmacodynamics of many drugs4; these differences involve more than simply a difference in body composition and size between men and women. The effects of these differences on clinical outcomes are substantial, as underscored by a reanalysis of data from a clinical trial of digoxin, which uncovered a previously unrecognized increase in mortality among women but not among men.5 Other examples of sex-based differences include responses to opioid analgesics and drugs that affect the potassium channels and the cardiac-conduction system.4,6 Every human cell has a pair of sex chromosomes, and this genetic difference is proving to have wide-ranging effects on gene expression.7 The full effect of sex difference on the metabolism and action of drugs is not known. Its importance, however, should not be overlooked in discussions of pharmacogenetics and pharmacogenomics.
7 ReferencesMolly Carnes, M.D.
University of Wisconsin, Madison, WI 537151
Weinshilboum R . Inheritance and drug response. N Engl J Med 2003;348:529-537
Full Text | Web of Science | Medline2
Evans WE ,McLeod HL . Pharmacogenomics -- drug disposition, drug targets, and side effects. N Engl J Med 2003;348:538-549
Full Text | Web of Science | Medline3
Goldstein DB . Pharmacogenetics in the laboratory and the clinic. N Engl J Med 2003;348:553-556
Full Text | Web of Science | Medline4
Woosley RL . From bench to bedside: role of gender-based therapeutics in the clinical care of women. J Womens Health 1998;7:21-23
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Rathore SS ,Wang Y ,Krumholz HM . Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-1411
Full Text | Web of Science | Medline6
Schwartz JB . Gender differences in response to drugs: pain medications. J Gend Specif Med 1999;2:28-30
Medline7
Ostrer H . Sex-based differences in gene expression. J Appl Physiol 2001;91:2384-2388
Web of Science | Medline
To the Editor:
Goldstein draws attention to the scientific obstacles facing the emerging field of pharmacogenomics. There are important nonscientific obstacles as well.1 For instance, federal regulators (accustomed to large clinical trials involving a diverse population of subjects and designed to test drugs that have substantial market potential, with centralized manufacturing and uniform labeling) will have to cope with a radically altered model of drug development and use. In the unlikely event that pharmacogenomics ushered in an era of complete customization, drug manufacturing would come to resemble the practice of pharmacy compounding that predominated a century ago.
Furthermore, payers may have limited enthusiasm for pharmacogenomics. After all, in the past, they have adopted economizing mechanisms, such as restricted drug formularies and therapeutic substitution, that work in a direction directly opposed to that of the tailoring of pharmaceutical therapies. As compared with research and development expenses for “off-the-rack” drugs, such expenses for customized medications would need to be recovered from a smaller population of users. In short, the success of pharmacogenomics may depend on the willingness of health insurers to pay a premium for improved therapeutic outcomes.
1 ReferencesLars Noah, J.D.
University of Florida College of Law, Gainesville, FL 32611-7625
noah@law.ufl. edu 1
Noah L . The coming pharmacogenomics revolution: tailoring drugs to fit patients' genetic profiles. Jurimetrics J 2002;43:1-28
Medline
Author/Editor Response
Drs. Padrini and Ferrari and Dr. Carnes appropriately emphasize that many factors beyond inheritance contribute to individual variation in drug response. I agree. Indeed, very early in my article, I point out that “individual differences in drug response can result from the effects of age, sex, disease, or drug interactions.” Achieving the goal of truly “individualized drug therapy” will require that physicians take all of these factors into account when deciding on a specific drug, dose, and route of administration. However, the dramatic developments that have occurred in genomic science now promise to provide health care professionals with objective information with regard to the contribution of genetics to variation in drug response. That information will have to be added to knowledge of the effects of age, sex, environment, disease, and possible drug interactions to reach the final therapeutic decision — a decision that should be based on principles of rational therapeutics.
Richard Weinshilboum, M.D.
Mayo Clinic, Rochester, MN 55905
weinshilboum.richard@mayo. edu Author/Editor Response
We certainly agree with Dr. Carnes that sex is an important variable that can influence drug disposition and effects, as are a number of other factors (e.g., age, drug interaction, environmental exposure, and diet). Although each of these factors has been shown to influence the effects of drugs in humans, through either genetic or nongenetic mechanisms, they were not within the scope of our article. Furthermore, there are many other determinants of gene expression and function, such as chromatin structure, gene methylation, and imprinting, that were also beyond the scope of our article. Our focus was on genetic polymorphisms that have been shown to alter drug disposition and effects in humans, without bias related to the chromosomes on which the affected genes reside. However, for reasons that are not fully understood, “nature” has been curiously biased against human sex chromosomes when distributing genetic polymorphisms. The Human Genome Project revealed substantially fewer single nucleotide polymorphisms (SNPs) on sex chromosomes than on autosomes, with only 4.7 and 1.5 SNPs per 10 kb of DNA on the X and Y chromosomes, respectively, as compared with 7.5 SNPs per 10 kb throughout the entire human genome.1,2 This lower level of genetic diversity on sex chromosomes and the small size of the Y chromosome most likely contribute to the paucity of sex-linked pharmacogenetic traits in humans.
2 ReferencesWilliam E. Evans, Pharm.D.
St. Jude Children's Research Hospital, Memphis, TN 38101-0318
william.evans@stjude. org Howard L. McLeod, Pharm.D.
Washington University Medical School, St. Louis, MO 63110-10931
Sachidanandam R ,Weissman D ,Schmidt SC , et al. A map of human genomic sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001;409:928-933
CrossRef | Web of Science | Medline2
Chakravarti A . To a future of genetic medicine. Nature 2001;409:822-823
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Author/Editor Response
Noah suggests that applications of pharmacogenetics may be constrained by the unwillingness of health care providers or insurers to pay a premium for improved therapeutic outcomes. In fact, it is easy to see how overall costs for health care providers could be reduced by pharmacogenetics. For drugs that work in only a minority of patients and drugs whose response cannot be assessed immediately (e.g., many anticancer agents), health care providers sometimes end up paying for medicines that do not benefit patients. The advance identification or narrowing of the pool of patients without a response to particular therapies would save money. The avoidance of adverse reactions would also result in immediate cost savings, as well as health benefits, as has already been illustrated in the case of mercaptopurines.1 In short, we do not believe that pharmacogenetics will lead to a conflict between the interests of patients and those of health care providers.
The economics are more complicated for drug companies, because markets may be segmented. But there are also potential advantages, including the possibility that the ability to predict who will have an adverse reaction to a drug or to identify an effective response that might be missed in an unselected cohort will result in smaller and less expensive trials and approval for drugs that would otherwise be rejected.2
The translation of basic pharmacogenetic research into clinically useful diagnostic tools will be challenging. But we do not see substantial economic barriers against the eventual clinical application of pharmacogenetic research.
2 ReferencesDavid B. Goldstein, Ph.D.
Patrick Vallance, M.D.
University College London, London WC1E 6BT, United Kingdom
dgoldstein@ucl.ac. uk 1
Weinshilboum R . Inheritance and drug response. N Engl J Med 2003;348:529-537
Full Text | Web of Science | Medline2
Roses AD . Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Disc 2002;1:541-549
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
David S. Jones, Roy H. Perlis. (2006) Pharmacogenetics, Race, and Psychiatry: Prospects and Challenges. Harvard Review of Psychiatry 14:2, 92-108
CrossRef2
Anton F Fliri, William T Loging, Peter F Thadeio, Robert A Volkmann. (2005) Analysis of drug-induced effect patterns to link structure and side effects of medicines. Nature Chemical Biology 1:7, 389-397
CrossRef
