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Pharmacogenomics: Challenges and Opportunities

Dan M. Roden, MD; Russ B. Altman, MD, PhD; Neal L. Benowitz, MD; David A. Flockhart, MD, PhD; Kathleen M. Giacomini, PhD; Julie A. Johnson, PharmD; Ronald M. Krauss, MD; Howard L. McLeod, PharmD; Mark J. Ratain, MD; Mary V. Relling, PharmD; Huijun Z. Ring, PhD; Alan R. Shuldiner, MD; Richard M. Weinshilboum, MD; Scott T. Weiss, MD, Pharmacogenetics Research Network
[+] Article and Author Information

From Vanderbilt University, Nashville, Tennessee; Stanford University Medical Center, Stanford, California; University of California, San Francisco, San Francisco, California; Indiana University, Indianapolis, Indiana; University of Florida, Gainesville, Florida; Children's Hospital Oakland Research Institute, Oakland, California; University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of Chicago, Chicago, Illinois; St. Jude Children's Research Hospital, Memphis, Tennessee; SRI International, Menlo Park, California; University of Maryland, Baltimore, Maryland; Mayo Clinic, Rochester, Minnesota; and Channing Laboratory, Boston, Massachusetts.


Acknowledgments: The authors thank Rochelle Long, Dina Paltoo, and Eileen Dolan for their comments on earlier versions of the manuscript.

Grant Support: Sites in the Pharmacogenetics Research Network are supported by the following U01 awards: GM61373, GM61390, GM74492, HL69757, GM61393, GM63340, HL65962, GM74518, GM61388, DA20830, and HL65899. The Pharmacogenetics and Pharmacogenomics Knowledge Base created by the network is housed at http://www.pharmgkb.org and is supported by U01 GM61374.

Potential Financial Conflicts of Interest:Consultancies: D.M. Roden (GlaxoSmithKline, Pfizer Inc., AstraZeneca, Abbott Laboratories, Novartis, 1st Genetic Trust), R.M. Krauss (Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Merck & Co. Inc., Pfizer Inc., International Dairy Foods Association), M.J. Ratain (Prometheus, Genzyme Corp., Genentech), R.M. Weinshilboum (National Institutes of Health); S.T. Weiss (Glaxo-Wellcome, Roche Pharmaceuticals, Millennium Pharmaceuticals, Genetech, Schering-Plough, Variagenics, Genome Therapeutics, Merck Frost); Honoraria: D.M. Roden (GlaxoSmithKline, Pfizer, Inc., AstraZeneca, Abbott Laboratories, Novartis, 1st Genetic Trust), Dr. Krauss (Kos Pharmaceuticals, Pfizer); Stock ownership or options (other than mutual funds): M.J. Ratain (Variagenics, Nuvelo, Applera); Grants received: D.M. Roden (1st Genetic Trust), R.M. Krauss (King, Merck & Co. Inc., Schering-Plough, Pfizer Inc.), H.L.M. Leod (National Institutes of Health), M.J. Ratain (National Institutes of Health), R.M. Weinshilboum (Eli Lilly Inc.); S.T. Weiss (Glaxo Wellcome, AstraZeneca, Pfizer Inc.); Grants pending: D.M. Roden (GlaxoSmithKline), M.J. Ratain (National Institutes of Health); Patents received: M.J. Ratain (National Institutes of Health), M.V. Relling (National Institutes of Health); Patents pending: M.J. Ratain (National Institutes of Health); Royalties: D.M. Roden (Genaissance), M.J. Ratain (National Institutes of Health).

Requests for Single Reprints: Dan M. Roden, MD, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285B, MRB4, Nashville, TN 37232; e-mail, dan.roden@vanderbilt.edu.

Current Author Addresses: Dr. Roden: Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285B, MRB4, Nashville, TN 37232-0575.

Dr. Altman: Department of Genetics, Stanford University Medical Center, 300 Pasteur Drive, Lane L301, Mail Code 5120, Stanford, CA 94305-5120.

Dr. Benowitz: University of California, San Francisco, Box 1220, 1001 Potrero Avenue, San Francisco General Hospital, 30 3316, San Francisco, CA 94143-1220.

Dr. Flockhart: Indiana University, 1001 West 10th Street, W-7123, Indianapolis, IN 46202.

Dr. Giacomini: University of California, San Francisco, 1550 4th Street, Mission Bay GD 584, San Francisco, CA 94143-2911.

Dr. Johnson: University of Florida, 1600 Southwest Archer Road, Room PG-22, Gainesville, FL 32610-0486.

Dr. Krauss: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609.

Dr. McLeod: University of North Carolina, Chapel Hill, Campus Box 7360, 3203 Kerr Hall, Chapel Hill, NC 27599-7360.

Dr. Ratain: University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637-1470.

Dr. Relling: St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105.

Dr. Ring: SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025.

Dr. Shuldiner: Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 West Redwood Street, HH-Room 494, Baltimore, MD 21201.

Dr. Weinshilboum: Mayo Clinic, 200 First Street SW, Rochester, MN 55905.

Dr. Weiss: Channing Laboratory, Brigham & Women's Hospital, 181 Longwood Avenue, Boston, MA 02115.


Ann Intern Med. 2006;145(10):749-757. doi:10.7326/0003-4819-145-10-200611210-00007
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The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.

Figures

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Figure 1.
The concept of pharmacogenetics.

Pharmacokinetics focuses on large clinical effects of single gene variants in small numbers of patients. However, the concept of pharmacogenomics examines many genomic loci, including large biological pathways and the whole genome, to identify variants that together determine variability in response to drug therapy.

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Figure 2.
Two types of variability in drug action.

Top. Volunteers received 10 mg of the CYP2D6 substrate debrisoquine, and the ratio of urinary concentrations of the parent drug and its 4-hydroxy metabolite in urine were determined. This experiment identifies at least 2 distinct populations, extensive and poor metabolizers, separated at the antimode (arrow). Redrawn with permission from reference 10. Bottom. Change in FEV1 in 1117 participants in 3 different trials of antiasthmatic therapy (inhaled steroids). Although the responses vary markedly, from an apparently deleterious drug effect to a highly beneficial one, there is no antimode. Redrawn with permission from reference 11.

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Clinical laboratory needs for pharmacogenomic testing
Posted on February 1, 2007
Alan H.B. Wu
University of California, San Francisco
Conflict of Interest: None Declared

In their review, Roden et al. present an excellent clinical "primer" for defining pharmacogenomics, including current research challenges and those drugs that might benefit from clinical pharmacogenomic testing. While the review clarifies many of these issues, we note relatively little discussion regarding the real world application of pharmacogenomics in the clinical setting.

The ordering of any clinical laboratory test should be accompanied by the question, "How will this test impact upon my decision, including that associated with selection of drug and dose?" While of academic interest to know whether a patient is a slow, intermediate, or rapid drug metabolizer, this information may not be relevant in the clinic setting. As an example, a colon cancer patient with a UGT1A1 *7/*7 genotype may be at risk for irinotecan-induced neutropenia (see Table 2 of review). What should be the oncologist's response to this data? Should the dose be decreased in response to this information? If a decreased dose is recommended, how much lower? Should this genotype result in a selection of different chemotherapeutic regimen? Outcome studies are critically needed to validate the utility of these genomic tests. The finding of an association between drug response and genetic variants represents the first step toward offering a clinical laboratory genomic testing service.

One potential use of pharmacogenomic data is toward the establishment of algorithms which might guide decisions regarding drug and/or dose. Development of algorithms requires integration of genotypic variables and other important patient demographics. As an example, algorithms have been developed based on age, gender, ethnicity, body size, and CPY 2C9 and VKORC1 genotype to predict the optimal initial warfarin dose to achieve optimum anticoagulation as measured by the prothrombin time and calculation of the International Normalized Ratio (2). These algorithms have not yet been approved by the Food and Drug Administration (FDA), and must be validated in the clinical setting. Draft, non-binding guidance documents issued by the FDA regarding multi-marker analysis have been released and may ultimately assist manufacturers toward the creation of interpretative algorithms (3).

Discovery of novel pharmacogenomic markers and targets involves the use of gene sequencing and large SNP (single nucleotide polymorphism) arrays. These are expensive, require specialized research equipment and operator training, and are therefore difficult to implement in routine clinical laboratory practice. Fortunately, commercialization of equipment designed for clinical laboratory practice may result in lower-cost reagents dedicated to specific pharmacogenomic applications. When these platforms and tests are approved by the FDA, practical implementation of pharmacogenomics in the clinical setting can commence.

Roden et al. (1) question how can pharmacogenetic information be incorporated into product labels that inform clinicians and patients. While such information does not currently exist in product labels for approved drugs today, the FDA Center for Drug Evaluation and Research and the Clinical Pharmacology Subcommittee of the Advisory Committee on Pharmaceutical Science has taken a different approach. The FDA will require the relabeling of irinotecan, warfarin, and tamoxifen, stating that genotyping is recommended prior to initial dosing. Unfortunately, guidance from the FDA regarding the interpretation and use in clinical practice is not yet available. Nevertheless, these mandates have become a major impetus for personalized medicine for manufacturers of pharmacogenomic tests and clinical laboratories. We anticipate that these mandates will also motivate physicians to order these tests avoid adverse medication events and/or for medical legal reasons. Practical regulatory issues remain for those clinical laboratories considering such services. These include validation studies (e.g., versus bidirectional sequencing), establishment of a quality control program, proficiency testing, etc., all elements required by CLIA. The College of American Pathologists has instituted a proficiency testing program to begin in 2007 which will be very helpful in assisting laboratories wishing to conduct pharmacogenomic testing.

While the cost for performing the test likely will decline due to increased competition among vendors, perhaps a more important issue is reimbursement. At the present, there are payment codes for individual steps involved with pharmacogenomic testing, DNA extraction, amplification, and individual SNP detection; however, these reimbursements costs are relatively modest. Importantly, no CPT codes currently exist that are specific to pharmacogenomic testing. Unless the cost of the testing decreases or the reimbursement for testing increases, widespread implementation of laboratory-based personalized medicine will be limited. Increased research efforts linking pharmacogenomic testing with patient outcomes, as well as changes in regulatory agencies and reimbursement policy are urgently needed to allow for increased utilization of pharmacogenomic testing in the clinical setting.

1. Roden DM, Altman RB, Benowitz NL, et al. For the Pharmacogenetics Research Network. Pharmacogenomics: challenges and opportunities. Ann Intern Med 2006;145:749-757.

2. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 gnetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106:2329-22.

3. U.S. Food and Drug Administration. In vitro diagnostic multivariate index assays. http://www.fda.gov/cdrh/oivd/guidance/1610.pdf

Conflict of Interest:

None declared

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