To the Editor: The review by Weinshilboum on the inheritanceof drug response (Feb. 6 issue)1 focuses on the pharmacogeneticsof drug metabolism as an important factor in the variabilityof drug effects among persons. An aspect of this topic thatis not often addressed is the variability among patients (representingthe majority) who carry wild-type alleles responsible for metabolizingenzymes. Responses to two drugs exemplify this variability.According to a recent study,2 metabolic clearance of warfarinin patients who are homozygous for the wild-type CYP2C9 alleleranges from about 130 ml per minute to 1500 ml per minute. Thesame applies to fluorouracil, an antineoplastic agent metabolizedby the polymorphic enzyme dihydropyrimidine dehydrogenase, whichexhibits remarkable variability in plasma clearance even amongpatients without an inherited deficiency of dihydropyrimidinedehydrogenase,3 because of dose- and time-dependent pharmacokinetics.4These two examples do not diminish the importance of geneticfactors, but they do indicate that acquired and environmentalfactors may be equally or even more important in explainingvariability in the effects of drugs.
Roberto Padrini, M.D. Mariano Ferrari, M.D. University of Padua 35131 Padua, Italy roberto.padrini{at}unipd.it
References
Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529-537. [Free Full Text]
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][ISI][Medline]
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][ISI][Medline]
Terret C, Erdociain E, Guimbaud R, et al. Dose and time dependencies of 5-fluorouracil pharmacokinetics. Clin Pharmacol Ther 2000;68:270-279. [Medline]
To the Editor: The articles on pharmacogenomics by Weinshilboum1and by Evans and McLeod2 and the accompanying editorial by Goldstein3fail to mention sex as a major genetic difference affectingpharmacokinetics and pharmacodynamics. There is considerableresearch on the effects of sex differences on the pharmacokineticsand pharmacodynamics of many drugs4; these differences involvemore than simply a difference in body composition and size betweenmen and women. The effects of these differences on clinicaloutcomes are substantial, as underscored by a reanalysis ofdata from a clinical trial of digoxin, which uncovered a previouslyunrecognized increase in mortality among women but not amongmen.5 Other examples of sex-based differences include responsesto opioid analgesics and drugs that affect the potassium channelsand the cardiac-conduction system.4,6 Every human cell has apair of sex chromosomes, and this genetic difference is provingto have wide-ranging effects on gene expression.7 The full effectof sex difference on the metabolism and action of drugs is notknown. Its importance, however, should not be overlooked indiscussions of pharmacogenetics and pharmacogenomics.
Molly Carnes, M.D. University of Wisconsin Madison, WI 53715
References
Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529-537. [Free Full Text]
Evans WE, McLeod HL. Pharmacogenomics -- drug disposition, drug targets, and side effects. N Engl J Med 2003;348:538-549. [Free Full Text]
Goldstein DB. Pharmacogenetics in the laboratory and the clinic. N Engl J Med 2003;348:553-556. [Free Full Text]
Woosley RL. From bench to bedside: role of gender-based therapeutics in the clinical care of women. J Womens Health 1998;7:21-23. [Medline]
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. [Free Full Text]
Schwartz JB. Gender differences in response to drugs: pain medications. J Gend Specif Med 1999;2:28-30. [Medline]
Ostrer H. Sex-based differences in gene expression. J Appl Physiol 2001;91:2384-2388. [Free Full Text]
To the Editor: Goldstein draws attention to the scientific obstaclesfacing the emerging field of pharmacogenomics. There are importantnonscientific obstacles as well.1 For instance, federal regulators(accustomed to large clinical trials involving a diverse populationof subjects and designed to test drugs that have substantialmarket potential, with centralized manufacturing and uniformlabeling) will have to cope with a radically altered model ofdrug development and use. In the unlikely event that pharmacogenomicsushered in an era of complete customization, drug manufacturingwould come to resemble the practice of pharmacy compoundingthat 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 tailoringof pharmaceutical therapies. As compared with research and developmentexpenses for "off-the-rack" drugs, such expenses for customizedmedications would need to be recovered from a smaller populationof users. In short, the success of pharmacogenomics may dependon the willingness of health insurers to pay a premium for improvedtherapeutic outcomes.
Lars Noah, J.D. University of Florida College of Law Gainesville, FL 32611-7625 noah{at}law.ufl.edu
References
Noah L. The coming pharmacogenomics revolution: tailoring drugs to fit patients' genetic profiles. Jurimetrics J 2002;43:1-28.
Dr. Weinshilboum replies: Drs. Padrini and Ferrari and Dr. Carnesappropriately emphasize that many factors beyond inheritancecontribute to individual variation in drug response. I agree.Indeed, very early in my article, I point out that "individualdifferences in drug response can result from the effects ofage, sex, disease, or drug interactions." Achieving the goalof truly "individualized drug therapy" will require that physicianstake all of these factors into account when deciding on a specificdrug, dose, and route of administration. However, the dramaticdevelopments that have occurred in genomic science now promiseto provide health care professionals with objective informationwith regard to the contribution of genetics to variation indrug response. That information will have to be added to knowledgeof the effects of age, sex, environment, disease, and possibledrug 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{at}mayo.edu
Editor's note: Dr. Weinshilboum reports having provided consultingservices to Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly,and Johnson and Johnson; all fees for these services are paidto the Mayo Foundation.
Drs. Evans and McLeod reply: We certainly agree with Dr. Carnesthat sex is an important variable that can influence drug dispositionand effects, as are a number of other factors (e.g., age, druginteraction, environmental exposure, and diet). Although eachof these factors has been shown to influence the effects ofdrugs 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 wason genetic polymorphisms that have been shown to alter drugdisposition and effects in humans, without bias related to thechromosomes on which the affected genes reside. However, forreasons that are not fully understood, "nature" has been curiouslybiased against human sex chromosomes when distributing geneticpolymorphisms. The Human Genome Project revealed substantiallyfewer single nucleotide polymorphisms (SNPs) on sex chromosomesthan on autosomes, with only 4.7 and 1.5 SNPs per 10 kb of DNAon the X and Y chromosomes, respectively, as compared with 7.5SNPs per 10 kb throughout the entire human genome.1,2 This lowerlevel of genetic diversity on sex chromosomes and the smallsize of the Y chromosome most likely contribute to the paucityof sex-linked pharmacogenetic traits in humans.
William E. Evans, Pharm.D. St. Jude Children's Research Hospital Memphis, TN 38101-0318 william.evans{at}stjude.org
Howard L. McLeod, Pharm.D. Washington University Medical School St. Louis, MO 63110-1093
Editor's note: Dr. Evans became a member of the Clinical Genomics Advisory Board of Merck and a member of the Scientific AdvisoryBoard for Signature Genetics and Gentris after the review articlewas written, and he was formerly a member of the ScientificAdvisory Board of PPGX. He currently serves as a consultantto Bristol-Myers Squibb. He holds no equity positions in anyof these companies. Dr. Evans's laboratory is supported by NationalInstitutes of Health grants. He receives no research supportfrom public or private companies. Dr. McLeod's laboratory issupported by grants from the National Institutes of Health,as well as by research grants from Novartis Pharmaceuticalsand Ortho Clinical Diagnostics for projects that do not overlapdirectly or indirectly with the contents of the article.
References
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][Medline]
Chakravarti A. To a future of genetic medicine. Nature 2001;409:822-823. [CrossRef][Medline]
Dr. Goldstein and a colleague reply: Noah suggests that applicationsof pharmacogenetics may be constrained by the unwillingnessof health care providers or insurers to pay a premium for improvedtherapeutic outcomes. In fact, it is easy to see how overallcosts for health care providers could be reduced by pharmacogenetics.For drugs that work in only a minority of patients and drugswhose response cannot be assessed immediately (e.g., many anticanceragents), health care providers sometimes end up paying for medicinesthat do not benefit patients. The advance identification ornarrowing of the pool of patients without a response to particulartherapies would save money. The avoidance of adverse reactionswould also result in immediate cost savings, as well as healthbenefits, as has already been illustrated in the case of mercaptopurines.1In short, we do not believe that pharmacogenetics will leadto a conflict between the interests of patients and those ofhealth care providers.
The economics are more complicated for drug companies, becausemarkets may be segmented. But there are also potential advantages,including the possibility that the ability to predict who willhave an adverse reaction to a drug or to identify an effectiveresponse that might be missed in an unselected cohort will resultin smaller and less expensive trials and approval for drugsthat would otherwise be rejected.2
The translation of basic pharmacogenetic research into clinicallyuseful diagnostic tools will be challenging. But we do not seesubstantial economic barriers against the eventual clinicalapplication of pharmacogenetic research.
David B. Goldstein, Ph.D. Patrick Vallance, M.D. University College London London WC1E 6BT, United Kingdom dgoldstein{at}ucl.ac.uk
References
Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529-537. [Free Full Text]
Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Disc 2002;1:541-9.
Fliri, A. F., Loging, W. T., Thadeio, P. F., Volkmann, R. A.
(2006). Analysis of Drug-Induced Effect Patterns: Linking Structure and Effect of Medicines. aacredbook
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