(SEATTLE) – Five hundred thousand women in the U.S. are taking tamoxifen to prevent breast cancer recurrence. Almost half of them have a gene variation that reduces the effectiveness of the drug. For patients with this gene variation, alternative treatments with higher success rates are available. In 2006, an FDA advisory panel recommended updating the tamoxifen label to reflect this important information. However, this update has not been made, even though three additional studies have confirmed the importance of genetic testing for tamoxifen since then.

Ten percent of women have a gene variation which prevents them from producing the enzyme CYP2D6 which is essential for tamoxifen effectiveness. In another thirty-five percent with a gene variation the production of this enzyme is reduced which impedes the effectiveness of tamoxifen. A study published this month in JAMA, the Journal of the American Medical Association, reported that these classes of patients had, respectively, a 29% and 20.9% recurrence rate compared to 14.9% for patients without this gene variation.

“We need to remember that these aren’t just numbers, these are women we care about. These are our sisters, and mothers, and friends,” said Howard Coleman Genelex Corporation’s CEO. “We need to start using the tools we have available to ensure that their cancer treatment is as successful as possible.”

National Foundation of Cancer Research (NFCR) has a long history of funding innovative research in the fight against cancer. NFCR is also committed to making sure new technologies are reaching patients who need them. NFCR is working with Genelex to increase awareness of factors, such as this gene variation, which diminish the effectiveness of tamoxifen. NFCR and Genelex also are promoting awareness of alternative treatments for patients who do not respond well to tamoxifen.

“It takes time to move a technology from bench to bedside. When it comes to DNA testing to determine if breast cancer patients are likely to benefit from tamoxifen, that wait needs to end,” stated NFCR President Franklin C. Salisbury, Jr.

Even in patients who do not have this gene variation, the effectiveness of tamoxifen may be impeded inadvertently. Numerous studies have shown that interactions with many prescription medicines, over-the-counter medicines, and even herbal remedies can reduce tamoxifen effectiveness.

Genelex Corporation offers Tamoxitest which provides an assessment of both risks to tamoxifen effectiveness. Interpretive software included with results alerts patients and their physicians if tamoxifen benefit is at risk as a result either of the gene variation discussed above or interactions with medicines and herbal remedies.

Los Angeles oncologist Dr. Michael Benjamin, MD is one of the first physicians to embrace this technology.  “The Genelex gene profiling technology is a powerful tool to help my patients.  With tamoxifen testing, we can appropriately individualize treatment based on patients’ ability to process the medicine.”

Benjamin regularly advises his patients to take Tamoxitest. “Genelex tamoxifen testing helps me be smarter about who I treat with tamoxifen, and why.  I can take the discoveries made in their labs right to the patient’s bedside,” states Benjamin. “I see it as the wave of the future in medicine.”

Maura, a breast cancer patient, says that she ordered Tamoxitest after she was diagnosed.  Her healthcare professionals did not discuss Tamoxitest with her. Rather, Maura learned about this valuable test on the Internet. Found to be an intermediate metabolizer, Maura and her doctor opened a dialogue about her dose of tamoxifen.  “It was worth the information – and peace of mind – I received,” she concluded.  Most insurance companies cover the test.

Breast cancer patients and healthcare providers can learn more about Tamoxitest at www.Tamoxitest.com. 

The National Foundation for Cancer Research’s website is www.NFCR.org.

Dr. Michael Benjamin’s website is www.interactMD.com

Reporters seeking comment, or an interview, may call Kristine Ashcraft, Genelex Corporation, at (206) 826-1957 or Erin Chen, National Foundation of Cancer Research at  (301) 961-9116.

JAMA released more research today that further confirms the importance of CYP2D6 testing to determine tamoxifen efficacy. Full details at http://jama.ama-assn.org/cgi/content/short/302/13/1429.

The conclusion:
Recurrence Rates:
14.9% for extensive metabolizers
20.9% for intermediate metabolizers
29.0% for poor metabolizers

This means that Extensive Metabolizers will get the same preventative outcome from tamoxifen as much more expensive aromatase inhibitor that have the added risk of potential bone and joint effects.

My take, Tamoxitest CYP2D6 testing is ready for prime time. It’s a win-win for patient, physicians, and payers – reduced costs and improved outcomes!

The tragic death of Michael Jackson has the potential to create an important “learning moment” for physicians and patients. According to the Journal of American Medical Association, adverse drug reactions are the “4th to 6th leading cause of death” in the US. The published reports of Mr. Jackson’s medications illustrate an important issue- any two drugs may be safe in combination but the cumulative effect of many drugs can be difficult to detect and very dangerous, especially in people with reduced drug processing capacity.

Jessica Oesterheld, MD is one of the authors of the best selling Clinical Manual of Drug Interaction Principles for Medical Practice. After analyzing the purported medication list she noted that “many of the concentrations of these drugs would have been dangerously increased.” Propofol often causes accidental death in recreational users. Interactions between propofol and many of the drugs Jackson is alleged to have been taking, such as Paxil, Zoloft and the opioid pain medicines Demerol, Vicodin, and Dilaudid, increase the potential dangers of those drugs.

Dr. Oesterheld’s experience with adverse drug reactions led her to collaborate with Dr. Robert Patterson, a fellow clinical psychiatrist and computer programmer. Together they developed GeneMedRx, a tool for analyzing the cumulative effect of the many factors leading to adverse drug reactions including prescription drugs, over-the-counter medicines, foods, herbal preparations, recreational drugs, and genetics that are missed by other drug interaction programs. The dangers inherent in Michael Jackson’s purported drug regimen would have been even greater for individuals with a positive DNA drug sensitivity test who comprise more than half of the population. DNA Drug Sensitivity Testing detects the up to 1000-fold person-to-person differences in drug processing capacity. You can see the “hidden” interactions GeneMedRx predicts at www.HealthandDNA.com/Jackson.

Michale Jackson's purported medication list

Genelex Corporation, Seattle, Washington is a DNA testing laboratory dedicated to reducing the high levels of morbidity and mortality that result from adverse drug reactions by personalizing medicine with the combination of DNA Drug Sensitivity Testing and GeneMedRx software.

Pharmacogenomics J. 2009 May 19.

Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening?
Laika B, Leucht S, Heres S, Steimer W.

Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, München, Germany.

The cytochrome P450 2D6 (CYP2D6) isoenzyme metabolizes about 25% of clinically used drugs. The impact of CYP2D6 metabolizer status on therapeutic outcome was assessed in 365 psychiatric in-patients treated with neuroleptics or antidepressants. Length of hospitalization and response onset were prolonged for patients receiving CYP2D6 drugs.
Intermediate metabolizers (IMs) receiving CYP2D6 doses above the population median had more side effects after 4 weeks than extensive metabolizers with above-median doses (9/13, 69% vs 4/23, 17%, P=0.003), than IMs with below-median doses (5/22, 23%, P=0.012) and IMs with other medication (24/84, 29%, P=0.009). The Clinical Global Impression scale response was lower for IMs treated with CYP2D6 drugs (3/42, 7%) than for IMs with other medication (21/84, 25%, P=0.017) probably due to increased side effects.
Identification of IM status (38% of study population) may help to reduce side effects and length/cost of hospitalization. Thus, not only poor and ultrarapid metabolizer but also IMs may benefit from CYP2D6 genotyping.
This is of paramount interest since it greatly improves cost/benefit estimations for pretreatment CYP2D6 screening.The Pharmacogenomics Journal advance online publication, 19 May 2009; doi:10.1038 /tpj.2009.23 .

PMID: 19451914

Drug Metab Dispos. 2008 Dec 12
Talakad JC, Kumar S, Halpert JR. University of California San Diego.

Cytochrome P450 (CYP) 2B6 metabolizes a number of clinically relevant drugs and is one of the most highly polymorphic human P450 enzymes, with the Lys(262)–>Arg substitution being especially common in several genetic variants. Therefore, K262R (2B6*4) was created in the CYP2B6dH background (N-terminal modified and C- terminal His tagged) and expressed in E. coli. The recombinant CYP2B6dH and K262R were purified and studied to investigate the effect of the Lys(262)– >Arg substitution with six of the most potent drug inhibitors of CYP2B6, namely clopidogrel, clotrimazole, itraconazole, raloxifene, sertraline and ticlopidine. K262R showed a > 3-fold increase in the Ki values with clopidogrel, itraconazole, and raloxifene and ~ 6-fold increase in Ki with sertraline, compared with CYP2B6dH. Similarly, K262R showed 2-, 4-, and > 20-fold higher Ks values than CYP2B6dH with clopidogrel, sertraline, and itraconazole, respectively. In contrast, when tested with several known type II inhibitors of CYP2B enzymes, K262R showed a 10-fold lower IC50 with 4-(phenyl)pyridine and ~2-fold lower IC50 with 4-(4-nitrobenzyl)pyridine or 1-(4-phenyl) benzylimidazole than CYP2B6dH. Subsequent analysis predicted possible in vivo drug-drug interactions between the CYP2B6 substrate efavirenz and drug inhibitors clopidogrel, clotrimazole, itraconazole, sertraline, and ticlopidine. Furthermore, Q172H/K262R (2B6*6), which is the most common genetic variant of CYP2B6 harboring K262R, was created in CYP2B6dH, expressed, purified, and characterized for inhibition. Q172H/K262R showed a > 6-fold increase in Ki with sertraline and clopidogrel compared with CYP2B6dH. The results suggest that individuals, especially homozygotes, with the 2B6*4 or 2B6*6 allele might be less susceptible to drug interactions resulting from P450 inhibition.

PMID: 19074527

Mayo gave a presentation yesterday at the 31st annual San Antonio Breast Cancer Symposium that further confirms the importance of the liver enzyme CYP2D6 in tamoxifen effectiveness. Tamoxifen is often prescribed to block the effects of estrogen in breast tissue to prevent breast cancer recurrence in ER+ (estrogen receptor positive) cancers which require estrogen to grow and spread. Previous studies have already revealed that tamoxifen is less effective in women with reduced CYP2D6 activity caused by genetic variations or co-administration with medications that inhibit CYP2D6, but the mechanism of action for tamoxifen was not well understood.

Tamoxifen is a pro-drug that is metabolized and converted into the metabolites endoxifen and 4HT; both previously believed to play a key role in suppressing estrogen. However, Mayo’s study shows that endoxifen degrades estrogen receptors in breast cancer cells and is the key metabolite involved in the effectiveness of tamoxifen. Since CYP2D6 is the enzyme that converts tamoxifen to endoxifen; this study further indicates that widespread genotyping and medication management can improve outcomes for many of the 35% of ER positive breast cancer patients who currently fail tamoxifen treatment.

On October 18, 2006, an FDA Advisory Subcommittee was convened to review the tamoxifen research findings to date and to make a recommendation regarding a label change. The consensus of the Subcommittee was that the label should be updated to reflect the fact that  postmenopausal women with ER-positive breast cancer who are CYP2D6 poor metabolizers treated with tamoxifen (by genotype or drug interaction) are at increased risk for breast cancer recurrence. This label change has still not been made, and now the case is even stronger.

So, what can be done with this information to reduce the risk of breast cancer recurrence?
 

First, genotyping should be considered for every ER-positive breast cancer patient taking tamoxifen. Insurance typically covers testing, and alternative therapies exist for treatment for the 10% of patients who are CYP2D6 poor metabolizers.

Second, medication management involving the careful monitoring of tamoxifen co-administration with other medications, herbals, and over-the-counters needs to happen. For example, “hot flashes,” a common side effect of tamoxifen, are typically treated with selective serotonin reuptake inhibitors, and fluoxetine, paroxetine and high doses of sertraline are notoriously potent CYP2D6 inhibitors. Additionally, 35% of patients are CYP2D6 intermediate metabolizers and are at risk with less potent inhibitors of CYP2D6 such as the commonly used herbal goldenseal as shown in the interaction report below. 

Tamoxifen, Goldenseal, CYP2D6 intermediate metabolizer interaction report

Genelex includes access to GeneMedRx drug and gene interaction software with each tamoxifen CYP2D6 test so healthcare providers and patients can quickly see if co-administration is going to reduce CYP2D6 activity.

Mayo’s study has confirmed the critical role of CYP2D6 in tamoxifen treatment. It is time to start putting this research to use in the clinic.

Today is the last day to express your opinion on whether warfarin (Coumadin) DNA testing should be covered by insurance. Please post your comments on this important decision which will have far reaching effects on the field of personalized medicine and pharmacogenetics. Please go to http://www.cms.hhs.gov/mcd/viewtrackingsheet.asp?from2=viewtrackingsheet.asp&id=224& to learn more about this study. To post your comments scroll to the bottom of the page and click on view public comments, then click on the orange comments button on the upper right of the page. 

Here is what Genelex’s CEO, Howard Coleman posted:

Thank you for the opportunity to comment on the importance to patients of insurance reimbursement for warfarin DNA testing.

Warfarin (Coumadin) therapy is expanding rapidly in the elderly population because of the increasing prevalence of atrial fibrillation and longer life spans. Numerous studies have documented that warfarin is underutilized in eligible patients. Physicians, while knowing that warfarin is effective, have fear about bleeding that may prevent its use. Physicians also have been shown to reduce their prescribing of warfarin after one of their patients experiences a bleeding event. Approximately 5 million patients currently take warfarin and 500,000 start this medicine every year. It is the seventh most frequently prescribed medicine in the US. Many anticoagulation experts believe that up to 50% more patients could benefit from taking warfarin, but don’t because of the fear of the adverse outcomes of minor and major bleeds, or the inconvenience of frequent blood testing and the costs of travel and lost productivity.

Warfarin is a difficult and hazardous drug to prescribe because of its extremely narrow therapeutic index and twenty-fold variation in individual patient dose requirement. Non genetic factors, such as age, gender and body weight account for approximately 12% of this unusually wide variation in individual stable dose requirement. Most patients are started on 5mg per day and asked to return to the clinic weekly, or more frequently for INR blood testing (international normalization ratio based on prothrombin time) and dose adjustment, if needed. At the time of patient visits, prescribers don’t know if the blood levels of warfarin are stable, going up or going down. The result is an inefficient, trial and error process if multiple INRs and dosing adjustments are required to achieve a stable maintenance dose. It puts patients at risk, especially when initiating warfarin and can take weeks or months to get the maintenance dose reliably and consistently right.

The elderly are especially at risk which is not appreciably mitigated by prescribers taking age into account. The severity of the risks of taking warfarin leads to 58,000 emergency room visits by patients over age 65 every year. It is second only to insulin in precipitating medication related ER visits and is listed by the FDA’s Adverse Event Reporting System in the top ten of drugs with the greatest number of serious adverse events. The risks of warfarin therapy are so great that in 2006 the FDA added a “black box” warning to the label (see below). More information is needed in the elderly when starting warfarin in order to reduce costs and the reduction in quality of life resulting from adverse events.

Many studies in the last five years have demonstrated that patients prescribed warfarin and carrying variations in genes that reduce the clearance of warfarin via CYP2C9, or affect the sensitivity of its treatment target VKORC1 are at double or triple the risk for an adverse bleeding event or treatment failure (odds ratios up to 5X) in the time period after starting warfarin. Variation in these genes is the most important causal mechanism of warfarin intersubject variability. Therefore, the relationship between genotype and clinical outcomes of, INR control, number of INR blood tests required to reach a stable dose, number of dosing adjustments and time in therapeutic INR range is not empirical or due to chance.

These risk elevating genetic variations are present in the majority of patients seen by clinicians and as many as 60% of patients would benefit from genetic testing. Compared to patients without these variations they take as much as three months longer to reach a stable dose after starting warfarin, and spend more time at risky high doses or sub therapeutic low doses as dosing adjustments in response to unacceptable INRs are made by the prescriber. The quality of anticoagulant control, in turn, is related to the risk of having an adverse event. Mounting clinical studies from around the world, and between various ethnic groups, including large prospective trials, confirm the basic facts outlined here. These studies also point to the usefulness of genetic testing in helping patients avoid the personal hardship of a bleeding related hospitalization or recurrence of a stroke, myocardial infarction or thromboembolism. Compared to age, body weight and gender, genetic factors contribute three times more information about variability in stable dosage requirements, 35% for CYP2C9 and VKORC1 versus 12% for age, gender and body weight.

Some suggest that we wait for the conclusions to be reached by additional studies that are underway before taking action. These studies may further refine our knowledge of how best to prescribe warfarin, and are unlikely to overturn the conclusions of the many studies completed so far and cited below. In addition these studies, conducted under controlled conditions, may not be applicable to the primary or secondary medical care that is received by most warfarin patients in the US. Allowing these or other future studies to be the gatekeeper to the implementation of warfarin DNA testing is not in the best interest of patients.

DNA testing of CYP2C9 and VKORC1 to help determine the maintenance dose of warfarin has been available from licensed medical laboratories since before 2000. There are now several FDA approved DNA diagnostic tests of high quality for warfarin dosing on the market. These tests are readily available and with the short turnaround time needed during the initiation of warfarin therapy. Prescribers can act on the test results because algorithms that incorporate DNA testing results and a variety of currently recognized clinical factors and drug interactions are available that can account for up to 79% of the individual dose variation. They can also predict the maintenance dose to within a milligram per day. These tests do not replace INR testing but have been shown to reduce the frequency needed for INR tests by improving the prediction of stable maintenance dose. In August 2007 the FDA changed the Coumadin drug label to point out the impact individual genetic variation has on warfarin dose requirement and risk.

One of the last remaining barriers to the routine adoption and availability of warfarin dosing DNA testing to the elderly patient is reliable and consistent insurance reimbursement. Estimates of cost effectiveness suggest that almost $1000 per patient could be saved by routine use of warfarin DNA testing at a cost of $550 per test, consistent with the costs of other routinely prescribed genetic tests. As testing volumes increase the costs of warfarin genetic testing will drop, further increasing its cost-effectiveness. These estimates did not take into account the added costs of more frequent monitoring and dosing adjustments by health care providers or the personal costs to patients. In addition, the psychological impact on patients to improve warfarin compliance will be enhanced by knowing that their prescriber has done all they can to start warfarin safely.

If the Center for Medicare and Medicaid Services adopts a policy of reimbursement for warfarin DNA testing, the virtually unanimous body of evidence collected for more than a decade points to a net result of a reduction in adverse events, treatment failures and costs. If CMS declines to reimburse for warfarin DNA testing it will be a major set-back for pharmacogenetic based personalized medicine and more importantly the millions of patients who will be denied the utility of this test and suffer accordingly as we have seen by published reports of the risks and bleeding complications in elderly patients treated with warfarin.

In summary, the weight and quality of evidence supports genetic testing for 2C9 and VKORC1 gene variants in elderly patients before or shortly after starting warfarin to improve the quality of anticoagulation and define starting doses that are closer to the eventual stable maintenance doses of warfarin. I recommend that CMS seriously consider reimbursement for these tests.

Abstracts of key papers.

A recent summary of previous trials, the benefit of genetic testing to various measures of quality anticoagulation and their conclusions about risks of bleeding can be found in “The critical path of warfarin dosing: finding an optimal dosing strategy using pharmacogenetics.” Clin Pharmacol Ther, 2008 Sep;84(3):301-3 by LJ Lesko, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, FDA is available at http://www.nature.com/clpt/journal/v84/n3/full/clpt2008133a.html 

These papers were published following recent FDA labeling changes (see below for excerpts).  They have also not been included in previous assessments of genetic testing to guide warfarin therapy such as the California Technology Assessment Forum which covers published literature to December 2007.

The largest prospective warfarin-treated cohort supports genetic forecasting.

Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, Holm L, McGinnis R, Rane A, Deloukas P.: Blood. 2008 Jun 23

Genetic variants of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose, but the effect of other genes has not been fully elucidated. We genotyped 183 polymorphisms in 29 candidate genes in 1496 Swedish patients starting warfarin treatment, and tested for association with response. CYP2C9*2 and *3 explained 12% (p=6.63×10(-34)) of the variation in warfarin dose, while a single VKORC1 SNP explained 30% (p=9.82×10(-100)). No SNP outside the CYP2C gene cluster and VKORC1 regions was significantly associated with dose after correction for multiple testing. During initiation of therapy, homozygozity for CYP2C9 and VKORC1 variant alleles increased the risk of over-anticoagulation, hazard ratios 21.84 (95%CI 9.46;50.42) and 4.56 (95%CI 2.85;7.30), respectively. One of eight patients with CYP2C9*3/*3 (12.5%) experienced severe bleeding during the first month compared with 0.27% of other patients (p=0.066). A multiple regression model using the predictors CYP2C9, VKORC1, age, gender and drug-interactions explained 59% of the variance in warfarin dose, and 53% in an independent sample of 181 Swedish individuals. In conclusion, CYP2C9 and VKORC1 significantly influenced warfarin dose and predicted individuals predisposed to unstable anticoagulation. Our results strongly support that initiation of warfarin guided by pharmacogenetics would improve clinical outcome.

Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.

Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE, Aquilante CL, Grosso L, Marsh S, Langaee T, Farnett LE, Voora D, Veenstra DL, Glynn RJ, Barrett A, McLeod HL. Clin Pharmacol Ther. 2008 Sep;84(3):326-31. Epub 2008 Feb 27

Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.

An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients.

Meckley LM, Wittkowsky AK, Rieder MJ, Rettie AE, Veenstra DL. Thromb Haemost. 2008 Aug;100(2):229-39

The objective of this study was to assess the relative influence of VKORC1 and CYP2C9 genetic variants on several clinical outcomes related to warfarin treatment. We conducted a retrospective cohort analysis of 172 anticoagulation clinic patients followed from warfarin initiation. We assessed the following clinical outcomes: time to stable dose; time in, above, and below therapeutic range; the probability of overanticoagulation (international normalized ratio [INR] >5); frequency of anticoagulation clinic visits; and the contribution of genetics to maintenance dose. Patients with CYP2C9 variants, compared to those without, achieved stable dose 48% later (p < 0.01), spent a higher proportion of time above range in the first month of therapy (14% vs. 25%, p = 0.07), and had a higher odds ratio (OR) of an INR >5 (OR: 4.15, p = 0.03). In contrast, the only statistically significant effect with VKORC1 was a higher odds of an INR >5 (OR: 4.47, p = 0.03) for patients homozygous for the VKORC1 low-dose haplotype (AA) compared to heterozygotes. We did not detect an influence of CYP2C9 nor VKORC1 on the frequency of clinic visits. CYP2C9 alone, VKORC1 alone, and a combination of genetic and clinical factors explained 12%, 27%, and 50%, respectively, of the variation in warfarin maintenance dose. In conclusion, genetic variation in VKORC1 appears to have a different influence than CYP2C9 on anticoagulation-related outcomes such as bleeding events and time in therapeutic range. This difference may be due, in part, to pharmacokinetics factors (e.g. drug half-life), which are influenced primarily by CYP2C9; these findings should be confirmed in additional studies.

Health Care Savings from Personalizing Medicine Using GeneticTesting: The Case of Warfarin

Andrew McWilliam, Randall Lutter and Clark Nardinelli Working Paper 06-23, November 2006 AEI-BROOKINGS JOINT CENTER FOR REGULATORY STUDIES.

Updated in Personalized Medicine (2008) 5(3): 279-284 confirming with sensitivity analysis that cost savings per patient who is tested genetically can be nearly $1000 per patient and improve health outcomes.

Executive Summary

Progress towards realizing a vision of personalized medicine—drugs and drug doses that are safer and more effective because they are chosen based on an individual’s genetic makeup has been slower than once forecast. The Food and Drug Administration has a key role to play in facilitating the use of genetic information in drug therapies because it approves labels, and labelsi nfluence how doctors use drugs. Here we evaluate one example of how using genetic information in drug therapy may improve public health and lower health care costs.

Warfarin, an anticoagulant commonly used to prevent and control blood clots, is complicated to use because the optimal dose varies greatly among patients. If the dose is too strong the risk of serious bleeding increases and if the dose is too weak, the risk of stroke increases. We estimate the health benefits and the resulting savings in health care costs by using personalized warfarin dosing decisions based on appropriate genetic testing. We estimate that formally integrating genetic testing into routine warfarin therapy could allow American warfarin users to avoid 85,000 serious bleeding events and 17,000 strokes annually. We estimate the reduced health care spending from integrating genetic testing into warfarin therapy to be $1.1 billion annually, with a range of about $100 million to $2 billion.

Excerpts from the most recent changes to the Coumadin (warfarin) labeling. The complete label is available at: http://www.fda.gov/cder/drug/infopage/warfarin/default.htm

Metabolism

The elimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4′-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin. NDA 9-218/S-105 Page 4

The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles CYP2C9*2 and CYP2C9*3 result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these allelles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively¹. Patients with one or more of these variant CYP2C9 alleles have decreased S-warfarin clearance (Table 1).²

Table 1. Relationship Between S-Warfarin Clearance and CYP2C9 Genotype in Caucasian Patients

CYP2C9 Genotype	N	S-Warfarin Clearance/Lean Body Weight (mL/min/kg) Mean (SD)a
*1/*1	118	0.065 (0.025)b
*1/*2 or *1/*3	59	0.041 (0.021)b
*2/*2, *2/*3 or *3/*3	11	0.020 (0.011)b
Total			188

Pharmacogenomics

A meta-analysis of 9 qualified studies including 2775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients.³ In this meta-analysis, 3 studies assessed bleeding risks and 8 studies assessed daily dose requirements. The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele.

In an observational study, the risk of achieving INR >3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of over anticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele.⁴ NDA 9-218/S-105 Page 5 Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined.⁵ About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication for warfarin therapy in Caucasian patients.⁵ Similar observations have been reported in Asian patients.^6,7

Selected References:

Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002;287:1690-8

Takahashi H, Wilkinson GR, Padrini R, Echizen H. CYP2C9 and oral anticoagulation therapy with acenocoumarol and warfarin: similarities yet differences. Clin Pharmacol Ther 2004;75:376-80.

Gage, B.F., Eby, C., Milligan, P.E., Banet, G.A., Duncan, J.R. & McLeod, H.L. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb. Haemost. 91, 87–94 (2004).

Aithal, G.P., Day, C.P., Kesteven, P.J.L. & Daly, A.K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353, 717–719 (1999).

Margaglione, M. et al. Genetic modulation of oral anticoagulation with warfarin. Thromb. Haemost. 84, 775–778 (2000).

Voora, D. et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb. Haemost. 93, 700–705 (2005).

Rieder, M.J. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med. 352, 2285–2293 (2005).

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Variations in the serotonin transporter gene SLC6A4 directly affect how patients respond to citalopram according to a Mayo Clinic Study just released in the current issue of the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics.

Researchers examined the serotonin transporter gene, or SLC6A4, in 1,914 study participants. The study showed that two variations in this gene have a direct bearing on how individuals might respond to citalopram. SLC6A4 produces a protein that plays an important role in achieving an antidepressant response.

In this study, researchers evaluated the influence of variations in SLC6A4 in response to citalopram treatment in white, black and Hispanic patients. Researchers found that white patients with two distinct gene variations were more likely to experience remission of symptoms associated with major depression. No associations between the two variations and remission were found in black or Hispanic patients.

According to the Centers for Disease Control and Prevention, antidepressants are the most prescribed medication in the country, but many stop taking their medication early because of negative side effects or lack of response. Pharamcogenetic testing looks at genetic variations like SLC6A4 that affect response so medications can be personalized for the patients to help avoid these treatment failures and side effects.

Dr. Mrazek, director of the Genomic Expression and Neuropsychiatric Evaluation (GENE) Unit at Mayo Clinic, stated “first, we started with trial and error – which feels like flipping a coin to select a medication. The Holy Grail would be to be able to consider the implications of variations in many genes. Ultimately, we hope to be able to determine with great accuracy which patients will respond to specific antidepressants and which patients will almost certainly not respond.”