Can We Identify Risk for Drug Toxicity?

October 10, 2013

October 10, 2013 – Very recently, David Kerr, Professor of Cancer Medicine at University of Oxford, in the United Kingdom, and past President of the European Society for Medical Oncology, talked on Medscape (see the video here) about risk-benefit analyses for novel, inventive cancer treatments. See here in italics his statement:

 When we talk about precision medicine and personalized medicine, it occurs to me that most of the discussion has been about benefits and seeing what we can do to better understand the cancer and the molecular biology of the tumor. Through that understanding, we would try to come up with biomarkers that allow us to select patient populations that are likely to receive added benefit.

 As Francis Collins has said, those of us who are in the cancer field are probably standard-bearers for the whole broad field of personalized medicine because of the steps that we have made in terms of linking molecular genotypes to phenotypes and identifying the people who respond better to drugs.

 However, a risk-benefit ratio implies 2 sides of the coin. It seems to me that perhaps we have been missing out in terms of considering the toxicology, the pattern of side effects. These will be determined not by the somatic tumor mutations that we use to identify biomarkers for benefit, but within the germline. How do we metabolize the drug? How do we excrete it? The absorption, distribution, and metabolism components become important. I believe that one way of improving the risk-benefit ratio is to reduce risk. If we had tools, if we had assays, if we had biomarkers to identify patients most at risk for toxicity, most at risk perhaps even for lethal toxicity, then we as an oncology community would adapt our therapy accordingly, possibly even omitting some drugs if the hazard ratio for death or lethality were very high, but more likely modulating the dose of the drug to see if we could obviate the need for inducing life-threatening grade 4 toxicities.

 There is an interesting play here. If we look at most modern, well-designed, phase 3 cancer treatment trials, sometimes including a couple of thousand patients, we are starting to get the statistics that may allow us to do some genome-wide association studies looking for patterns of genetic change in the germline — not in the tumor, but the germline. That may give us an idea about which patients are most at risk for certain adverse effects and tell us, as practicing physicians, to adjust the dose accordingly.

 It is a new science. I am going to call it tox-nostics. There you are. You have heard it here first. I am going to trademark the term. We need to do more concerted research to see if we can improve risk-benefit, but through the portal of reducing risk rather than focusing only on benefit. I think modern, well-designed trials in which germline DNA — ie, blood — has been collected, gives us a way of doing this.

 We know that some tests out there are moderately well used for 5-FU, for irinotecan.[1] I think we can improve on these. I think we can improve test performance, utility, availability. We just need a few clinical champions, a few good tests, to really make the difference.

 Thanks for listening. As always, we will be very happy to take any comments that you may care to make or to post. Medscapers, ahoy! Thank you.

 This is a very notable statement, not only for Medscapers. I would like to comment it on two accounts. First, I am not so sure whether the world has waited for the new term “tox-nostics” and whether a “trade marking” of it will be necessary and would successfully serve its purpose, namely to promote the concepts of targeted efficacy and safety of patient’s therapies. For one, “tox-“ (or any mentioning of toxicity) in the field of drug development and marketing is very negatively looked at and basically considered a “non do”.  Extensive and start-up company terminating (TheraSTrat AG to be precise (you may still search the net for it)) past experience of the author of this Blog would indicate that neither the phamaceutical industry, nor investors and financial markets, nor regulators and patients would like to hear anything near to toxicity in connection with their product and/or therapy.  On the other hand, we (and others), in the early years of the last decade, have coined the term “theragenomics” to embrace the concept of targeted efficacy and safety of patient’s therapies by applying genomic and individualized genetic knowledge to drug therapy.

 Secondly, on a far more positive note, the recently FDA-approved anti-melanoma drug Zelboraf (Vemurafinib) would be one of several good example in case for Prof. Kerr’s proposal/statement. Zelboraf (Vemurafinib) is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved companion genetic test. Zelboraf (Vemurafinib) is not indicated for treatment of patients with wild-type BRAF melanoma. That means in the clear that before treatment, patients need to be tested for this mutation (i.e. allelic variant of the tumor BRAF gene) by a companion gene test. Only those patients who test positive for the BRAF V600E variant are eligible for and will profit from a  treatment with Zelboraf (Vemurafinib).

 In the “Warnings and Precautions”-section of Zelboraf’s FDA-approved drug label, the following potential serious, if not fatal, adverse effects of Zelboraf are listed: New Primary Cutaneous Malignancies; New Non-Cutaneous Squamous Cell Carcinoma; Other Malignancies; Tumor Promotion in BRAF Wild-Type Melanoma; Serious Hypersensitivity Reactions; Severe Dermatologic Reactions, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN); QT Prolongation; Hepatotoxicity; Photosensitivity; Serious Ophthalmologic Reactions; Embryo-Fetal Toxicity. Here (at FDA) and here (at DailyMed), you will find the drug label on Zelboraf (Vemurafinib).

 The other listed severe drug effects not withstanding, at least for “Severe Dermatologic Reactions, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)” we know from many other drug which are associated with this adverse effect, that there seems to exist a genetic predisposition of patients to develop SJS and TEN. For example, patients carrying the HLA-B*5701 allele have a very high risk for developing SJS and TEN when treated with Ziagen (Abacavir). Likewise, patients carrying the HLA-B*1501 allele have a very high risk for developing SJS and TEN when treated with Carbamazepine-containing medications such as Tegretol, Equetro, Carbatrol, and generics thereof. For more information on SJS and TEN, you might want to consult the link here to get started.

 Here, with Zelboraf (Vemurafinib) it might be worthwhile to see, if one the HLA-alleles already associated with SJS or TEN also dispose individuals treated with Zelboraf (Vemurafinib) to SJS or TEN or if in this case, genome wide analysis (GWA) would be necessary to identify new (HLA) alleles predisposing according patients to SJS or TEN. In any case, using such procedures, clinicians might in already today be in the position to provide highly effective targeted therapies combined with targeted avoidance of severe, treatments limiting and/or fatal drug toxicities to at least some patients, all of which would be in line with Prof. Kerr’s statement.


Dabrafenib [Tafinalar] and Trametinib [Mekinist] Approved for BRAF V600 Mutated Metastatic Melanoma

May 30, 2013

May 30, 2013 – From a Medscape News Release we learn today that two new drugs have been approved by the US Food and Drug Administration (FDA) for use in certain patients with metastatic or unresectable melanoma, along with a diagnostic test to identify patients who are suitable for treatment.

The new products, Dabrafenib [Tafinalar] and Trametinib [Mekinist], were both developed by GlaxoSmithKline. Both are orally available tablets, but they have slightly different mechanisms of action.

Dabrafenib [Tafinalar]  acts as a BRAF inhibitor and is approved for use in patients with melanoma whose tumors express the BRAF V600E gene mutation. It is seen as being a next-generation product but is in the same class as the first BRAF inhibitor to reach the market, Vemurafenib [Zelboraf] (Genentech).

Trametinib [Mekinist] has a related but slightly different mechanism and acts as a mitogen-activated, extracellular signal-regulated kinase inhibitor (MEK inhibitor). It is the first drug in this class to be approved and is indicated for use in patients with whose tumors express the BRAF V600E or V600K gene mutations.

Approximately half of melanomas arising in the skin have a BRAF gene mutation, the FDA notes in its approval notice. Alongside the new drugs, the agency also approved a genetic test, the THxID BRAF test, a companion diagnostic developed in collaboration with bioMérieux that will help determine wither a patient’s melanoma cells have the V600E or V600K mutation in the BRAF gene.

Melanoma is the leading cause of death from skin disease, the FDA adds. The National Cancer Institute estimates 76,690 Americans will be diagnosed with melanoma and 9480 will die from the disease in 2013.

Clinical Trial Data

Dabrafenib [Tafinalar]  was approved on the basis of data from the BREAK 3 study, conducted in 250 patients with previously untreated BRAF V600 mutation–positive metastatic melanoma. It showed that in such patients, Dabrafenib [Tafinalar]  significantly improved the median progression-free survival compared with chemotherapy with dacarbazine (5.1 vs 2.7 months; P < .0001). These results were published in July 2012 issue of the Lancet (2012;380:358-365).

The FDA notes that the most serious adverse effects reported in patients receiving Dabrafenib [Tafinalar] included an increased risk for cutaneous squamous cell carcinoma, fevers that may be complicated by hypotension, severe rigors, dehydration, kidney failure, and increased blood sugar levels requiring changes in diabetes medication or the need to start medicines to control diabetes.

The most common adverse effects reported in patients receiving Dabrafenib [Tafinalar]  included hyperkeratosis, headache, fever, joint pain, noncancerous skin tumors, hair loss, and hand–foot syndrome.

The pivotal study for Trametinib [Mekinist], the METRIC study, was a little different in that it was conducted in 322 patients who had already tried a prior regimen of chemotherapy. In this study, compared with chemotherapy, Trametinib [Mekinist] significantly improved progression-free survival as well as overall survival. The results were published in the New England Journal of Medicine.

The FDA notes that the most serious adverse effects reported in patients receiving Trametinib [Mekinist]  included heart failure, lung inflammation, skin infections, and loss of vision. Common adverse effects included rash, diarrhea, tissue swelling (peripheral edema), and skin breakouts that resemble acne.

The agency also noted that women of childbearing years should be advised that Dabrafenib [Tafinalar]  and Trametinib [Mekinist]  carry the potential to cause fetal harm. Men and women should also be advised that both drugs also carry the potential to cause infertility.

Being Investigated in Combination

Dabrafenib [Tafinalar]  and Trametinib [Mekinist]  have been approved for use as monotherapy, and not as a combination treatment, the FDA has emphasized. However, there is a lot of interest from clinicians in using both drugs together, and indeed the manufacturer is conducting a clinical trial with the combination.

Preliminary results from a clinical trial with the combination suggest that use of the 2 drugs together resulted in less toxicity, and specifically in fewer secondary skin cancers, than has been seen with  Vemurafenib [Zelboraf]  used alone.

GlaxoSmithKline is now conducting a phase 3 study (known as COMBI-AD) of the combination of Dabrafenib [Tafinalar]  and Trametinib [Mekinist]  in patients with BRAF V600 melanoma that has been completely removed by surgery. Such patients are at high risk for relapse, and the combination of drugs is being tested to see whether it can delay or prevent the recurrence of melanoma, the company noted.

Problem: Responses Are Short-lived

The new Dabrafenib [Tafinalar]  appears to be similar to the already-marketed Vemurafenib [Zelboraf], but there are important differences between the 2 BRAF inhibitors in their toxicity profiles, noted Kim Margolin, MD, from the Seattle Cancer Care Alliance in Washington..

Skin toxicities, particularly the emergence of low-grade squamous cancers and keratoacanthomas, which occurred in a substantial number of patients taking Vemurafenib [Zelboraf], appear to be quite unusual with Dabrafenib [Tafinalar], Dr. Margolin noted. However, a systemic “pyrexia reaction,” which is almost never seen with Vemurafenib [Zelboraf], has been seen in a substantial percentage of patients taking Dabrafenib [Tafinalar]. “We don’t know yet about the off-target mechanisms of these differences and how much may be due to the vehicle or the formulation for each of these oral agents,” she added.

However, the biggest problem with the BRAF inhibitors in the treatment of melanoma has been the lack of durable response: These drugs “tend to work for an average of 5 to 6 months,” Dr. Margolin noted. What to do when patients fail on these drugs remains a challenge, she added.

Ultimately, combination therapy with a BRAF inhibitor (such as Vemurafenib [Zelboraf]  or Dabrafenib [Tafinalar]) plus a MEK inhibitor (such as Trametinib [Mekinist]) is “likely to be most valuable for improved and lasting results,” according to Dr. Margolin. Firstclinical results along these lines have been published in the New England Journal of Medicine at the end of last year.


Ivacaftor [Kalydeco] approved by FDA to treat the rare G551D mutant positive form of cystic fibrosis

February 3, 2012

February 03, 2012 – From a press release by the FDA, we just learn about e new success of the principle of personalized medicine. Please read the original article below:

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The U.S. Food and Drug Administration today approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene.

CF is a serious genetic disorder affecting the lungs and other organs that ultimately leads to an early death. It is caused by mutations (defects) in a gene that encodes for a protein called CFTR that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

CF, which affects about 30,000 people in the United States, is the most common fatal genetic disease in the Caucasian population. About 4 percent of those with CF, or roughly 1,200 people, are believed to have the G551D mutation.

“Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said FDA Commissioner Margaret A. Hamburg, M.D. “The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development.”

The FDA reviewed and approved Kalydeco in approximately three months under the agency’s priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy.

Kalydeco was approved ahead of the drug’s April 18, 2012 prescription user fee goal date and is designated as an orphan drug, which identifies the disease as affecting fewer than 200,000 people in the United States.

In patients with the G551D mutation, Kalydeco, a pill taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of CF such as increasing weight gain.

“Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This is a breakthrough therapy for the cystic fibrosis community because current therapies only treat the symptoms of this genetic disease.”

Two 48-week, placebo-controlled clinical studies involving 213 patients, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, were used to evaluate the safety and efficacy of Kalydeco in CF patients with the G551D mutation. In both studies, treatment with Kalydeco resulted in significant and sustained improvement in lung function.

Kalydeco is effective only in patients with CF who have the G551D mutation. It is not effective in CF patients with two copies of the F508 mutation in the CFTR gene, which is the most common mutation that results in CF. If a patient’s mutation status is not known, an FDA-cleared CF mutation test should be used to determine whether the G551D mutation is present.

The most common side effects of Kalydeco include upper respiratory tract infection, headache, stomach ache, rash, diarrhea, and dizziness.


EMA: Public consultation open on concept paper on pharmacogenomics in evaluation of authorised medicines

January 26, 2012

January 26, 2012 – I am relaying the information below by the EMA to the readers of this blog. It might be interessting to dwell into this concept paper (as a scientist, a treating physician, or an informed patient) for informations only or even for commenting.

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 The European Medicines Agency (EMA) has released a concept paper on the development of a guideline on the evaluation of pharmacogenomic methodologies in the evaluation of authorised medicines for public consultation.

The concept paper on key aspects for the use of pharmacogenomic methodologies in the pharmacovigilance evaluation of medicinal products explains that a proportion of the variability in response to medicines is due to genetic differences between individuals. Identifying individuals at risk of side effects, unexpected complications or lack of efficacy may help the development of strategies to optimise the use of medicines.

The concept paper sets out a number of issues that a future guideline could cover. These include the systematic consideration of the effects of genetic variability in safety monitoring of medicines, the use of biomarkers, the timing of the monitoring of genomic data and the information that should be provided in medicines’ product information.

The concept paper is open for comments until 15 March 2012. Comments should be sent to pgwpsecretariat@ema.europa.eu using the form for submission of comments.


Vemurafenib [Zelboraf] Approved Together with a Companion Diagnostic Test by FDA for Advanced Melanoma in BRAF V600E Positive Patients

August 20, 2011

August 17, 2011 — The US Food and Drug Administration (FDA) has just approved the oral targeted therapy Vemurafenib [Zelboraf] for the first-line treatment of both metastatic and unresectable melanomas. The drug is specifically indicated for patients with melanoma whose tumors have V600E mutations in the BRAF gene. An estimated 50% of patients with melanoma have this type of BRAF mutation, which does not occur in normal cells. The drug is not indicated for use in melanoma patients negative for the BRAF V600E mutation. Vemurafenib [Zelboraf] is a BRAF inhibitor that blocks the function of the V600E-mutated BRAF protein.

Vemurafenib [Zelboraf] has been approved with a companion diagnostic test that will help determine whether a patient’s melanoma cells have the BRAF V600E mutation. The first-of-a-kind test is known as the cobas 4800 BRAF V600 Mutation Test (by Roche Molecular Systems).

The approval of Vemurafenib [Zelboraf] and the cobas test is a great example of how companion diagnostics can be developed and used to ensure patients are exposed to highly effective, more personalized therapies in a safe manner,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostic Device Evaluation and Safety in the FDA’s Center for Devices and Radiological Health. The FDA’s approval of the cobas 4800 BRAF V600 Mutation Test was based on data from the same study that evaluated the safety and effectiveness of Vemurafenib [Zelboraf].

Vemurafenib [Zelboraf] was reviewed under the FDA’s priority review program that provides for an expedited 6-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists, says the agency.

“This has been an important year for patients with late-stage melanoma. Vemurafenib [Zelboraf] is the second new cancer drug approved that demonstrates an improvement in overall survival,” said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in a press statement. “In March, we approved Ipilimumab [Yervoy], another new treatment for late-stage melanoma that also showed patients live longer after receiving the drug.”


Reduced Effect from Clopidogrel [Plavix] in “Poor Metabolizer” Patients

June 12, 2010

Through a new boxed warning, the FDA is alerting healthcare professionals about a subgroup of patients who cannot effectively metabolize the anti-platelet drug Clopidogrel [Plavix].

These patients, called “poor metabolizers,” have little or no activity of the liver enzyme CYP2C19, which converts Clopidogrel [Plavix] to its active form, so they may not experience the full anti-clotting benefits of the drug.

Practitioners should know that tests are available to identify genetic differences in CYP2C19 function and thus identify poor metabolizers. They should consider using other anti-platelet medication or an alternative dosing strategy for these patients. And although raising the dose of Clopidogrel [Plavix] in poor metabolizers can increase anti-platelet response, an appropriate dose regimen has not been established in a clinical trial.

Please find additional information here:

The Original Article

FDA MedWatch Safety Alert. Plavix (clopidogrel): Reduced effectiveness in patients who are poor metabolizers of the drug. March 12, 2010.

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Gene Testing Helps Get Warfarin [Coumadin] Dose Right

March 22, 2010

March 21, 2010 – Doctors are reporting an exciting win for gene testing and personalized medicine: Checking patients’ DNA before starting them on a popular blood thinner helps get the tricky dose right and keep them out of the hospital.

The drug is warfarin, sold as Coumadin and in generic form as Warfarin. About 2 million Americans start on it each year to prevent blood clots after surgery or for other medical conditions. However, the world’s most common blood thinner is also one of its most dangerous drugs. One person’s ideal dose can be 10 times that of another’s. Even certain foods can throw dosing seriously off. Too much warfarin can lead to bleeding, too little can lead to clots, and either one can kill. Up to 20 percent of patients wind up in the hospital in their first six months on the drug.

Several companies sell tests for the two genes, CYP2C9 and VKORC, respectively, that control how warfarin is metabolized and binds to its receptor. But doctors wonder: Is it worth a $250-to-$400 test to guide the dose of a drug that costs less than $6 a month? A new study, presented Tuesday at an American College of Cardiology conference, suggests it is. Patients given gene tests to set their initial warfarin dose had about a 30 percent lower risk of being hospitalized than similar patients whose doses were set by trial and error.

“If we reduce just two hospitalizations per 100 patients tested, that more than compensates for the cost,” said the study’s leader, Dr. Robert Epstein. He is chief medical officer of Medco Health Solutions Inc., a New Jersey-based pharmacy benefits manager for many big insurance companies. For the study, researchers at the Mayo Clinic in Rochester, Minn., did gene tests on cells from cheek swabs of 896 patients in Medco plans who were starting on warfarin. Each patient’s doctor was given the results and advice on how to interpret them to set a dose. For a comparison group, researchers selected 2,688 similar patients from the same insurance plans who also were starting on warfarin and whose initial dose was set by the doctor’s best guess.

After six months, 18 percent of the gene-tested patients and 26 percent of the others had been hospitalized. That worked out to about a 30 percent lower risk for those given gene testing. “This may help make this a safer drug to utilize,” said Dr. James McClurken, chief of the cardiology conference and a heart surgeon at Temple University in Philadelphia.

Study leader Epstein said, “We’ve demonstrated that you can make warfarin work better with genetics.” Newer drugs seeking to compete with warfarin should include gene testing for dose-setting to make a fairer comparison, he said.

Medco paid for the gene tests and other study costs. Researchers from the Mayo Clinic donated their time. Results also are published in the Journal of the American College of Cardiology. Medco is doing another study to see whether gene testing can predict if a patient will do better on the anti-clotting drug Plavix or a competitor. On Friday, the U.S. Food and Drug Administration added its strongest warning to the label for Plavix because some patients with a gene variation in CYP2D6 cannot metabolize the drug, putting them at increased risk for heart attack and stroke.

This article is totally copyrights© 2010 The Associated Press (AP). All rights remain with AP.


FDA Drug Safety Communication: Reduced effectiveness of Clopidogrel [Plavix] in patients who are poor metabolizers (i.e. carriers of selected CYP2C19 allelic variants) of the drug

March 17, 2010

March 17, 2010 – The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the label for Clopidogrel [Plavix], the anti-blood clotting medication. The Boxed Warning is about patients who do not effectively metabolize the drug (i.e. “poor metabolizers”, see below) and therefore may not receive the full benefits of the drug.

The Boxed Warning in the drug label will include information to:

  • Warn about reduced effectiveness in patients who are poor metabolizers of Clopidogrel [Plavix]. Poor metabolizers do not effectively convert Clopidogrel [Plavix] to its active form in the body.
  • Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function.
  • Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in patients identified as poor metabolizers.

Clopidogrel [Plavix] is given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease. Clopidogrel [Plavix] works by decreasing the activity of blood cells called platelets, making platelets less likely to form blood clots.

For Clopidogrel [Plavix] to work, enzymes in the liver (particularly CYP2C19) must convert (metabolize) the drug to its active form. Patients who are poor metabolizers of the drug, do not effectively convert Clopidogrel [Plavix] to its active form. In these patients, Clopidogrel [Plavix] has less effect on platelets, and therefore less ability to prevent heart attack, stroke, and cardiovascular death. It is estimated that 2 to 14% of the population are poor metabolizers; the rate varies based on racial background.

Healthcare professionals should be aware that a subgroup of patients are poor metabolizers and do not metabolize Clopidogrel [Plavix] effectively; this can result in reduced effectiveness of Clopidogrel [Plavix]. Healthcare professionals should consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in these patients.

Patients should not stop taking Clopidogrel [Plavix] unless told to do so by their healthcare professional. They should talk with their healthcare professional if they have any concerns about Clopidogrel [Plavix], or to find out if they should be tested for being a poor metabolizer.

In May 2009, FDA added information about poor metabolizers of Clopidogrel [Plavix] to the drug label. However, based on additional data reviewed by the agency (see Data Summary below) the Boxed Warning is now being added to highlight the reduced effectiveness of Clopidogrel [Plavix] in these patients and to recommend that healthcare professionals consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in patients identified as poor metabolizers.

Additional Information for Patients and Health Care Providers Alike

Patients currently taking Plavix should:

  • Be aware that some patients do not convert Clopidogrel [Plavix] to its active form as well as other patients. These patients may not get the same benefit from Clopidogrel [Plavix]and are known as poor metabolizers.
  • Not stop taking Clopidogrel [Plavix] unless told to do so by their healthcare professional.
  • Talk with their healthcare professional if they have any concerns about Clopidogrel [Plavix].
  • Talk with their healthcare professional to see if testing to determine their metabolizer status is appropriate.

FDA recommends that healthcare professionals should:

  • Be aware that some patients may be poor metabolizers of Clopidogrel [Plavix]. They do not effectively convert Clopidogrel [Plavix] to its active form because of low CYP 2C19 activity.The effectiveness of Plavix as a preventive therapy is reduced in these patients.
  • Be aware that tests are available to determine patients’ CYP2C19 status.
  • Consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in patients who have been identified as poor metabolizers.
  • Be aware that although a higher dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response, an appropriate dose regimen for poor metabolizers has not been established in a clinical outcome trial.
  • Review the newly approved Clopidogrel [Plavix] drug label for complete information on the use of Clopidogrel [Plavix].

Scientific Background and Data Summary

The liver enzyme CYP2C19 is primarily responsible for the formation of the active metabolite of Clopidogrel [Plavix]. Pharmacokinetic and antiplatelet tests of the active metabolite of Clopidogrel [Plavix] show that the drug levels and antiplatelet effects differ depending on the genotype of the CYP2C19 enzyme. The following represent the different alleles of CYP2C19 that make up a patient’s genotype:

1. The CYP2C19*1 allele has fully functional metabolism of Clopidogrel [Plavix].

2. The CYP2C19*2 and *3 alleles have no functional metabolism of Clopidogrel [Plavix]. These two alleles account for most of the reduced function alleles in patients of Caucasian (85%) and Asian (99%) descent classified as poor metabolizers.

3. The CYP2C19*4, *5, *6, *7, and *8 and other alleles may be associated with absent or reduced metabolism of Clopidogrel [Plavix], but are less frequent than the CYP2C19*2 and *3 alleles.

A patient who carries two loss-of-function alleles (as defined above) will have poor metabolizer status.

The pharmacokinetic and antiplatelet responses to Clopidogrel [Plavix] were evaluated in a crossover trial in 40 healthy subjects. Ten subjects in each of the four CYP2C19 metabolizer groups (ultrarapid, extensive, intermediate and poor) were randomized to two treatment regimens: a 300 mg loading dose followed by 75 mg per day, or a 600 mg loading dose followed by 150 mg per day, each for a total of 5 days. After a washout period, subjects were crossed over to the alternate treatment. Decreased active metabolite exposure and increased platelet aggregation were observed in the poor metabolizers compared to the other groups. When poor metabolizers received the 600 mg loading dose followed by 150 mg daily, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen. Healthcare professionals should note that an appropriate dose regimen for patients who are poor metabolizers has not been established in clinical outcome trials.


Inherited risk factors increase odds of developing childhood acute lymphoblastic leukemia (ALL)

January 16, 2010

January 16, 2010 – This contribution has just been published in the ScienceBlog – Pharmacogenetics at this locoation. It is presented here in its original state and with all credentials and rights resting with the original author.

Scientists at St. Jude Children’s Research Hospital have identified inherited variations in two genes that account for 37 percent of childhood acute lymphoblastic leukemia (ALL), including a gene that may help predict drug response.

The findings stem from the first complete search of the human genetic blueprint or genome to look for inherited risk factors for ALL, the most common childhood cancer. Published in the August 16 advance online issue of Nature Genetics, the work offers the first proof based on a complete survey of the human genome that inheritance plays a role in childhood ALL.

Mary Relling, Pharm.D., St. Jude Pharmaceutical Sciences chair and the paper’s senior author, estimated that individuals who inherited variations in genes known as ARID5B or IKZF1 are almost twice as likely to develop ALL as those without the variations. Even then, she said, the risk remains low. ALL strikes roughly one in every 75,000 Americans. Sixty percent are children and teenagers.

“The genetic variations alone are not enough to cause the cancer. Like all cancers, pediatric ALL is a multi-factor disease,” Relling explained. “But these findings may give us a handle on the mechanism of the disease and drug responsiveness to it.”

Exactly the same genes, ARID5B and IKZF1, were confirmed to be altered in British children with ALL. That study was published by the Institute of Cancer Research in Surrey, England, in the same issue of Nature Genetics.

In the St. Jude study, researchers collaborated with colleagues from the Children’s Oncology Group (COG), who provided additional cases for genetic analysis. COG is an international group of medical institutions that cooperate in research studies and clinical trials of childhood cancer treatment.

Researchers scanned the genomes of 441 children with ALL and a control group of 17,958 cancer-free individuals for more than 300,000 common genetic variations known as single nucleotide polymorphisms or SNPs.

The search found 18 SNPs that differed significantly in frequency between individuals with and without ALL. Six of the 18 SNPs were associated with one of the four main subtypes of ALL.

The six included two SNPs linked to the ARID5B gene. About 11 percent of those in the control group inherit the leukemia-risk ARID5B variations from both mother and father, Relling said. In comparison, the same high-risk ARID5B SNPs were found in 38 percent of patients with a type of ALL known as hyperdiploid ALL. That subtype accounts for about 20 percent of ALL patients.

Three more SNPs were traced to the genes IKZF1 and DDC, which are next to each other on chromosome 7. IKZF1 is also known as IKAROS. Earlier research from St. Jude and COG linked acquired changes in IKZF1 to an increased risk of ALL relapse. The new evidence tying inherited variation in IKZF1 to an increased risk of developing ALL underscores the need for medications targeting variations in this gene, Relling said.

Both ARID5B and IKZF1 play important roles in normal development of lymphoid or white blood cells, she said. ARID5B belongs to a family of genes that make transcription factors, which help regulate gene activity. “If they have an inherited variation that affects the function of those genes, these are plausible pathways for how a normal lymphoid cell could be disrupted and transformed into a cancer cell,” Relling said.

Inherited variations in ARID5B might also influence patient response to chemotherapy, particularly to the drug methotrexate. “We found this same inherited variation also affected accumulation of the drug in leukemia cells. It accumulates better. That allows us to use a lower dose and still cure the leukemia,” Relling explained. “These findings may identify a new marker that could be used to help decide on doses of methotrexate in patients with varying ARID5B status.”

Scientists are not sure how the SNPs they identified influence cancer risk. But studies of variation in gene expression associated with the ARID5B gene indicate the inherited variations have a biological function. Researchers must still determine what it is.

Other authors of this paper include Lisa Trevino, Wenjian Yang, Deborah French, Geoffrey Neale, James Downing, Susana Raimondi, Ching-Hon Pui and William Evans, all of St. Jude; Stephen Hunger, University of Colorado, Denver; William Carroll, New York University Medical Center, New York; Meenakshi Devidas, University of Florida, Gainesville; and Cheryl Willman, University of New Mexico, Albuquerque.

This study was supported by the National Cancer Institute, the National Institutes of Health/National Institutes of General Medical Sciences Pharmacogenetics Research Network and ALSAC.

Blogged with the Flock Browser

Avoid Coadministration of Clopidogrel [Plavix] and Omeprazole [Prilosec] or Esomeprazole [Nexium]

November 18, 2009

November 17, 2009 – Today, the US Food and Drug Administration (FDA) informed on new data showing that the proton pump inhibitor (PPI) Omeprazole [Prilosec] or [Prilosec OTC] reduces the anti-blood clotting effect of Clopidogrel [Plavix] by almost half when these 2 medicines are taken by the same patient. Patients at risk for heart attacks or strokes who use Clopidogrel [Plavix] to prevent blood clots will not get the full effect of this medicine if they are also taking Omeprazole [Prilosec]; therefore, the FDA recommends that the coadministration of Omeprazole [Prilosec] and Clopidogrel [Plavix] be avoided.

The new recommendations, updated from a January 2009 Early Communication, are based on study results from the manufacturers of Clopidogrel [Plavix]. The studies confirm that coadministration of Omeprazole [Prilosec] with Clopidogrel [Plavix] results in decreased levels of Clopidogrel [Plavix]’s active metabolite, reducing Clopidogrel [Plavix]’s anticlotting effect.

Omeprazole [Prilosec] inhibits the drug-metabolising enzyme CYP2C19, which is responsible for the conversion of Clopidogrel [Plavix] into its active metabolite with anticlotting activity. The new studies compared the amount of Clopidogrel [Plavix]’s active metabolite in the blood and its effect on platelets in patients who took Clopidogrel [Plavix] plus Omeprazole [Prilosec] versus those who took Clopidogrel [Plavix] alone. A reduction in active metabolite levels of about 45% was found in those who received Clopidogrel [Plavix] with Omeprazole [Prilosec] compared with those taking Clopidogrel [Plavix] alone. The effect of Clopidogrel [Plavix] on platelets was reduced by as much as 47% in patients receiving Clopidogrel [Plavix] and Omeprazole [Prilosec] together. These reductions were seen whether the drugs were given at the same time or 12 hours apart.

Since the level of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with Clopidogrel [Plavix]. However, Esomeprazole [Nexium], a PPI that is the S-enantiomer of omeprazole and as such also contained in Omeprazole [Prilosec], inhibits CYP2C19 and should also be avoided in combination with Clopidogrel [Plavix].

Other stomach acid-reducing drugs, such as Ranitidine [Zantac], Famotidine [Pepcid], Nizatidine [Axid], or antacids, are not expected to interfere with the anticlotting activity of Clopidogrel [Plavix] because they do not inhibit CYP2C19 enzyme activity. However, Cimetidine [Tagamet] or [Tagamet HB] does inhibit CYP2C19 activity and should also not be used together with Clopidogrel [Plavix].

In addition to Cimetidine [Tagamet], other drugs that are potent inhibitors of the CYP2C19 enzyme would be expected to have a similar effect and should be avoided in combination with Clopidogrel [Plavix]. These include Fluconazole [Diflucan], Ketoconazole [Nizoral], Voriconazole [VFEND], Etravirine [Intelence], Felbamate [Felbatol], Fluoxetine, as [Prozac], [Sarafem], or  [Symbyax], Fluvoxamine [Luvox], and Ticlopidine [Ticlid].

Sanofi-aventis and Bristol-Myers Squibb, the makers of Plavix (Clopidogrel [Plavix]), are updating this drug’s label with the details of the studies and are conducting follow-up studies to further explore drug interactions with Clopidogrel [Plavix].

Until further information is available, FDA recommends the following:

• The concomitant use of Omeprazole [Prilosec] and Clopidogrel [Plavix] should be avoided because of the effect on Clopidogrel [Plavix]’s active metabolite levels and anticlotting activity. Patients at risk for heart attacks or strokes, who are given Clopidogrel [Plavix] to prevent blood clots, may not get the full protective anticlotting effect if they also take prescription drug Omeprazole [Prilosec] or Omeprazole [Prilosec OTC], its over the counter (OTC) form.

• Separating the dose of Clopidogrel [Plavix] and Omeprazole [Prilosec] in time will not reduce this drug interaction.

• Other drugs that should be avoided in combination with Clopidogrel [Plavix] because they may have a similar interaction include Esomeprazole [Nexium],  Cimetidine [Tagamet], Fluconazole [Diflucan], Ketoconazole [Nizoral], Voriconazole [VFEND], Etravirine [Intelence], Felbamate [Felbatol], Fluoxetine, as [Prozac], [Sarafem], or  [Symbyax], Fluvoxamine [Luvox], and Ticlopidine [Ticlid].

• At this time the FDA does not have sufficient information about drug interactions between Clopidogrel [Plavix] and PPIs other than Omeprazole [Prilosec] and Esomeprazole [Nexium] to make specific recommendations about their coadministration. Healthcare professionals and patients should consider all treatment options carefully before beginning therapy.

• There is no evidence that other drugs that reduce stomach acid, such as most H2 blockers Ranitidine [Zantac], Famotidine [Pepcid], Nizatidine [Axid] (except Cimetidine [Tagamet] or [Tagamet HB], which is potent CYP2C19 enzyme inhibitor), or antacids interfere with the anticlotting activity of Clopidogrel [Plavix]. Ranitidine and Famotidine are available by prescription and OTC to relieve and prevent heartburn and antacids are available OTC to relieve heartburn.

• Talk with your patients about the OTC medicines they take. Be aware that patients may be taking nonprescription forms of Omeprazole [Prilosec] and Cimetidine [Tagamet]. Likewise, patients are urged to inform their physicians if they take any of these OTC medicines.

The FDA will continue to investigate other drug interactions with Clopidogrel [Plavix]. The FDA plans on presenting this issue at the next meeting of the FDA’s Drug Safety Oversight Board in November. The Agency will communicate any further recommendations or conclusions once additional information is available.

Phamacogenetic considerations (added by the blog author)

Patients should be aware that even without taking any of the aforementioned  CYP2C19 enzyme-inhibiting co-medications, monozygote carriers of the loss of function CYP2C19*2, CYP2C19*3,  CYP2C19*4, and CYP2C19*5 allelic variants may experience a considerably reduced transformation of Clopidogrel [Plavix] to its pharmacologically active metabolite responsible for the anti-clotting activity. This may also be true for patients who are compound heterozygote carriers of such alleles, for example  CYP2C19*2/CYP2C19*3, etc. More information on this aspect can be found here and here.


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