Genetic Testing for Drug Compatibility

This is a copy of today's Living With TN Newsletter

Dear Member at Living With TN,

This is going to be a bit long and some of the vocabulary is dense. If you're having problems wading through, then please have a family member or friend read through with you.

Credit for this research goes to Dr. Mark Linskey, a prominent neurosurgeon at UC Irvine California, and his colleague, Rosene D. Pirrello, Pharmacist Specialist in Palliative Care at UC Irvine Health. I have added a few insights of my own.

This special edition of our newsletter was prompted by a question raised by a friend and TN patient, Dinah Federer. She had seen information on Millenium Inc, a company that does genetic testing to estimate the compatibility of a range of medications with individual patients. She wondered whether such testing has been demonstrated to be accurate and whether it is covered by medical insurance.


1. Chronic face pain patients are frequently treated off-label with anti-epilepsy (anti-seizure) drugs (AEDs) such as Carbamazepine (Tegretol), Oxcarbazepine (Trileptal), and Gabapentin (Neurontin). Severe or toxic side effects and medication ineffectiveness are wide-spread concerns among these patients.

2. Significant numbers of seizure patients are resistant to AED medication. Considerable genetics research is emerging to assess and explain medication resistance in treating seizure. While the mechanisms in chronic neuropathic or neuralgia pain are doubtless different from those operating in seizures, some research findings still seem of interest to chronic pain patients.

3. The long term potential for pharmacogenetic testing may be to tailor medication selection and dose levels to specific patients, based on genetic indications of compatibility. That potential has not yet been reliably realized in AEDs, due to highly variable results between multiple studies and even between types of seizures. One incidental result that has been noted, however, is that if a patient is resistant to one type of AED, then there is a strong likelihood that they will also be resistant to others -- even those which employ different metabolic mechanisms.

4. No single gene or mechanism accounts for all resistance to AEDs. Research continues, to better characterize genetic factors that may limit transport of AED active components from the GI tract into the blood stream, from the blood stream across the Blood-Brain Barrier, and then within the brain to particular receptor "targets".

5. The FDA has issued an alert to physicians, strongly recommending gene testing in patients with Asian or South Asian Indian heritage, prior to being placed on Carbamazepine. The alert will be reported as follows in the newest version of “Trigeminal Neuralgia” in the BMJ “Clinical Evidence” series authored by Dr. Joanna Zakrzewska and Dr. Mark Linskey.

Drug safety alert:

(2008, carbamazepine) — Carbamazepine is associated with a risk of potentially life-threatening skin reactions, including Stevens-Johnson syndrome. The risk of carbamazepine-induced Stevens-Johnson syndrome is greater in people with the allele HLA-B*1502. The frequency of this allele varies worldwide and is highest in some Asian populations. Individuals of Han Chinese, Hong Kong Chinese, or Thai origin should be screened for HLA-B*1502 before starting treatment with carbamazepine. [30] Those who test positive for HLA-B*1502 should not start carbamazepine treatment unless the benefits clearly outweigh the risk of Stevens-Johnson syndrome. [31]

Reference 30. Ferrell PB, Jr, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics 2008;9:1543–1546.[PubMed]

6. The following text is from "The clinical impact of pharmacogenetics on the treatment of epilepsy" Wolfgang Lo¨scher, Ulrich Klotz, Fritz Zimprich, and Dieter Schmidt, Epilepsia, 50(1):1–23, 2009.

"AEDs are one of the most common causes of cutaneous [skin] adverse drug reactions (cADRs). The manifestation of cADRs ranges from a mild maculopapular exanthema (MPE) to life-threatening severe cutaneous reaction (SCR), which includes Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug hypersensitivity syndrome (HSS). The incidence of AED-induced cADRs varies from drug to drug. Overall, isolated rash related to AEDs occurs in up to 10% of patients ... while the incidence of SCR is estimated to be 1 [in] 10,000 exposures. More than 90% of SCR occurs in the first 2 months of AED use (Zaccara et al., 2007). AEDs associated with increased risk of SCR include [Carbamazepine], [Phenobarbital], [Phenoitin] and [Lamotrigine]. cADRs represent a significant burden on the health care system, and SCR mortality reaches up to 30% (Svensson et al., 2001). Identification of genetic [factors] predisposing to development of AED-induced SCR offers the possibility of avoiding these high-risk drugs."

7. There are indications that Carbamazepine and Phenytoin may also be associated with elevated risk of neurological deformities in the babies of women taking these drugs during pregnancy. Pharmacogenetic testing appears to provide advance indicators of increased risk in at least a small number of women who may wish to consider other means of pain control during pregnancy, or even deferring children pending surgical relief of pain and elimination or reduction of AEDs.

I have not yet extended my reading to medical literature on use of pharmacogenetic testing in opioid medications. Nor am I yet aware of whether Medicare has extended a code to any specific testing regime or method, which would support medical insurance reimbursement for this process. Given the FDA warning, I would be very surprised if insurance did not reimburse.

My take-away understanding of this issue is that while anti-seizure medication is the first line of defense and pain management for chronic face pain patients, such medications are not risk free. A risk of one in ten thousand is small but highly consequential for that one. Appropriate testing before prescription and close monitoring during the first 90 days may significantly reduce this risk.

For further discussion of this subject, please feel free to print out this newsletter and share it with your primary care provider.

Another great article, Red. Hubby had that skin reaction on his legs

to Gabapentin. He's having the MVD operation on Sept 12th by Dr. Giannoti at USC Los Angeles.

Hi Red,

Thanks for raising awareness on pharmacogenetics. In my opinion our genetic make-up plays a huge role in how we respond to medications, supplements and nutrition's. I highly recommend everyone to get tested on their genetic predispositions. I believe in the saying, "Knowledge is Power" and knowing where you have weaknesses can be a blessing, as it allows you to take corrective actions.
FDA approved CYP450 genotyping testing in 2004 (info attached at the bottom of my comments). Since than numerous labs start performing genetic tests and most insurance companies are paying for them. Here is the list of the labs that I know for sure does this type of tests: Quest Diagnostics, Genova Diagnostics, Pathway Genomics, Doctor's Data, Sorenson Genomics, GeneSight and 23&Me (This company is the only one used to give a complete DNA analysis direct to consumer for $99. Since last fall they stopped their service by the FDA and now, they are going through an FDA approval process.)
Lets talk about AED's. They are Sodium Channel Blockers. Most SCN1A gene mutations causes a loss of function of the sodium channels, thereby making sodium channel blocking anti-epileptics a poor drug of choice for treatment. Giving sodium channel blocking drugs to patients with SCN1A mutations will further decrease the amount of inhibitory neurotransmitters in the brain, making the balance scale tip even more toward the seizure activity.
I had my DNA SNP's test completed with Sorenson Genomics and Genesight. In my case, I am heterozygous for the C677T polymorphism in the MTHFR gene which causes me to have a methylation defect in processing Folic Acid conversion. By knowing this defect and taking daily active folate supplements I can avoid abnormal methylation processes in my body. Like I said, knowledge is power and if the science is available, why not take an advantage of it to take better care of yourself.
Best regards,
Susan.


Roche AmpliChip Cytochrome P450 Genotyping test and Affymetrix GeneChip Microarray Instrumentation System - K042259

This is a brief overview of information related to FDA’s clearance to market this product.


Product Name : Roche AmpliChip Cytochrome P450 Genotyping test and Affymetrix GeneChip Microarray Instrumentation System
Manufacturer: Roche Molecular Systems, Inc. and Affymetrix, Inc.
Address: 4300 Hacienda Dr. , Pleasanton , CA 94588 and 3380 Central Expy. , Santa Clara , CA 95051
Clearance Date: December 23, 2004
Clearance Letter: http://www.accessdata.fda.gov/cdrh_docs/pdf4/k042259.pdf

What is it? The Roche AmpliChip Cytochrome P450 Genotyping test for use on the Affymetrix GeneChip Microarray Instrumentation System is a new laboratory test system that will help doctors personalize treatment options for their patients. Doctors can use a patient’s genetic information to help them determine appropriate drugs and doses to prescribe. This will help minimize harmful drug reactions and prevent patients from being improperly treated with sub-optimal doses.

This system uses DNA extracted from a patient’s blood to detect certain common genetic mutations that alter the body’s ability to break down (metabolize) specific types of drugs. The enzyme produced from the gene that is tested, called cytochrome P4502D6 (CYP4502D6), is active in metabolizing many types of drugs including antidepressants, antipsychotics, beta-blockers, and some chemotherapy drugs. Variations in this gene can cause a patient to metabolize these drugs abnormally fast, abnormally slow, or not at all. For example, the same dose that is safe for a patient with one variation might be too high (and therefore toxic) to a patient with a different variation who cannot metabolize the drug.

With genetic information for this gene, many harmful reactions resulting from inappropriate dosing and treatment may be significantly reduced as clinicians can adjust the patient’s regimen accordingly.

How does it work? A doctor orders the genetic test in patients to gather information on the predicted metabolic activity of their enzyme encoded by CYP4502D6.

  • A sample of blood is collected and taken to the lab.
  • The lab extracts DNA from the blood sample.
  • The lab processes and applies the DNA to the Cytochrome P450 Genotyping test.
  • The GeneChip Microarray Instrumentation System reads the test.
  • The genetic result for the Cytochrome P450 Genotyping test is sent to the doctor.
  • The doctor uses the Cytochrome P450 genetic test results, clinical evaluation and other lab tests as an aid in individualizing patient treatment options.

When is it used? The AmpliChip Cytochrome P450 Genotyping System is used to help a clinician determine if a patient has mutations in their CYP4502D6 gene that may affect their ability to metabolize certain drugs.

You should discuss these test results with your doctor because your body’s ability to metabolize a range of drug classes may be affected. This test is not a substitute for your doctor’s judgement and clinical experience. The test system is designed to aid the doctor in making individualized treatment decisions.

What will it accomplish? The AmpliChip Cytochrome P450 Genotyping System may help the doctor determine if a patient is at risk of adverse drug reactions or sub-optimal drug response.

When should it not be used? The AmpliChip Cytochrome P450 Genotyping System should not be used:

  • As the only test to determine specific drug dose. Other clinical information and patient history should primarily be considered.
  • To aid in predicting a patient’s drug response for drugs that are not metabolized by the enzyme encoded by Cytochrome P4502D6.
  • To aid in predicting a patient’s response to drugs for which the mutant Cytochrome P4502D6 phenotype has not been clearly established.

Susan. You've offered a lot of information. For our members, please inform us of whether you work for or otherwise represent any of the companies mentioned in your post.

Likewise all other readers: please be advised that no single gene or allele governs all processes involved in drug absorption. There is still a lot of basic science to be discovered in this area. If you believe that you are either hypersensitive or potentially allergic to a drug or drugs, then consult with your doctor concerning whether genomic testing may be appropriate.

Red,


To answer your question. No, I am not affiliated with any of the companies that I mentioned on my blog, neither do I own any stocks or will make any financial gain from any mentioned companies! My sole purpose was to share my view on Pharmacogenomics and my research with fellow TN sufferers. I am a retired RN by profession and afflicted with TN for 8 yrs.
You started this discussion on this forum and I thought I would just pitch in some of my personal experience and knowledge with the forum and your readers. Maybe this was a mistake on my part because I am offended by your suspicious remarks. Instead of a simple "Thank you for sharing your view" you are questioning my integrity. From now on maybe it is best that I keep my knowledge and research to my self.
V/r
Susan

Susan,

No personal slam on you was offered or intended. We've had problems with spammers trying to penetrate the site and solicit our members. So my intuitive caution as well as the question itself are pertinent. As an retired RN you surely understand that. You've seen some of the more outrageous and sometimes harmful claims made for various products in the so-called "alternative medicine" industry, just as I have.

It's not a mistake here to share your own experience or professional expertise. When it comes to product advocacy, others who read this thread have a right to know where the information comes from and whether a potential conflict of interest may be at work. I'm happy to see from your most recent note that it is not.

Regards, Red

Susan,

Thank you for providing this information for our members. You are not being singled out here in this thread, and no offense was intended or given. It can be a rough ride for Moderator's. We are damned if we do, and damned if we don't. We have to quantify information such as shared by you, to fulfill our roles here. That means that integrity and assurance can be held by you, me and indeed all the other members here.

Again thank you for sharing and quantifying this information which may help our members.

Jackie

Hi Susan

Thanks for your thorough and informative post . , I echo the comments of Red and Jackie. Spammer questions can lead us onto thin ice. I have gotten wet on several occasions. One of the limitations of cyberspace is the inability to hear the tone of one's comments and, at times, misinterpretations arise .It is unfortunate when it occurs. However, within our community, when misunderstandings occur they can be quickly repaired. We suffer enough with "The Dreaded Disorder". Hopefully, this is the case today.

You have been member long enough to know the invaluable participation of Red. Without his contribution, our community could not maintain the level of professionalism we have. Every one of his postings is the best interests of our community..

Susan, please allow me a bit of candidness and don't be offended. You've done a lot of research and provided very useful information. You are a TN sufferer. Even if you are miffed at one of us, why would you not share your work with the rest of us?

Thank you for your contribution Stick around: Living with TN is a good place to be.

Best regards

Bill

This was very interesting. I have mysteriously developed what has been called Rosasea, with an acute sensitivity to sunlight since taking carbamezapine and Neurontin . Very annoying. Hopefully someday we will be a progressive enough society, with a real sense of social responsibility to medical conditions like TN, and genetic testing for drug sensitivity will be procedural for all patients. Thank you for this information. I spent last Friday in the ER with an allergic reaction to Flexeril. Could not breathe and broke out in hives and shook so badly I could not hold a pencil. I had taken the drug previously before I began taking the anti-seizure drugs with no issues. What we also need to explore is what chemical changes occur within us as we take these drugs. Not the obvious like liver or kidney issues, but tremors, mood swings ect. Thank you again. I will be undergoing an MVD on Tuesday after my failed Gamma. But I did have a wonderful year before it failed. On to the next challenge.

Dear Red, Jackie & Bill,

Thank you for your reply and clarification. I fully understand your duties and charter to protect your readers from spammers and individuals trying to make financial gain from us TN sufferers. I apologize too if I came across too strong.

I will continue offering my views on this forum and answer any questions to best of my ability. As I mentioned earlier, I’ve consulted many medical experts on my condition and I become so frustrated with many of them. Their lack of knowledge or expertise push me to spent so much time on my own researching, reading and even keeping a pain journal of my periodic attacks.

Thank you for providing TN sufferers this forum to exchange information and to ventilate their feelings and frustrations!

All the best!

Susan

Susan, thank you for your understanding. As everyone here either suffers or cares for someone who does, our continued friendship is vital.

Jackie

Edster, your reply was logged blank. Did you wish to add something?

This is the future of health care. For many illnesses, like cancer, treatment can be so specific that only infected cells are targeted. It's all about quality of life issues. Thank you for bringing the article to everyone's attention.My doctor just did a DNA test on me to look at the reactions with my medications. It didn't shed much light now I have it. I also did the testing myself with 23 and Me to look for any connections. I think only time will tell if everyone would just leave me alone and allow me to heal.

Richard, were you satisfied with the quality of your genetic test results from 23 and Me? Unfortunately last year I miss the boat on getting mine done before the FDA suspended their services. For time being they are only providing ancestry analysis and going through the FDA approval process on the medical part. I sure hope they get a green light from FDA soon and still charge $99. What a bargain!

richard_scott said:

This is the future of health care. For many illnesses, like cancer, treatment can be so specific that only infected cells are targeted. It's all about quality of life issues. Thank you for bringing the article to everyone's attention.My doctor just did a DNA test on me to look at the reactions with my medications. It didn't shed much light now I have it. I also did the testing myself with 23 and Me to look for any connections. I think only time will tell if everyone would just leave me alone and allow me to heal.

I am so glad that more attention is being paid to this.
First off, I am just a teacher. NO affiliation to any clinic, university, or lab. But I have a son with Tourette Syndrome, Chiari Malformation, Intracranial Hypertension, a shunt, and chronic pain.
He also has multiple medication sensitivities. We thought he just had an ever-growing list of medications that he was “allergic” to. We had multiple trips to the ER for serious reactions.
Finally, his wise neurologist suggested we have him tested for medication sensitivity.
Wow. It changed our lives.
The test is for the Cytochrome P450 set of liver enzymes that are necessary for breaking down medications.
Scientists are constantly finding new enzymes, as well.

A person who manufactures too much of an enzyme will metabolize a medication very quickly. This could be explained by people who say that pain medication does “nothing” for them, or that the effects only last for about an hour. It’s because they are metabolizing too quickly.

However, in the case of my son, he lacks three key enzymes that are known to break down certain drugs, including some pain killers, Risperidol (which he was given for his Tourette’s) and several others.

So what happens is that in his body a lack of enzymes means the medication cannot be broken down. It appears as though he is having an allergic reaction when he really just has a toxic level of medication in his body.
Since we had this test done, he has never had another “allergic” reaction to medications!
He has a lot of serious medical issues, so I never travel without my handy P450 chart, which shows all the meds he simply cannot metabolize.

Now, here is the scary part: most physicians have never heard of this! Hospital pharmacists are very helpful, but other physicians have never heard of this and so therefore look at me as if I am crazy when I tell them that he can’t metabolize certain drugs! I was even shocked to find out that not all residents were taught this in med school!
Thankfully, the hospital where he gets his care is aware of this and very good about checking “the list” before prescribing something.

I truly think this is more common than we realize. We all know people who have bizarre reactions to medications. My own grandmother could take nothing without having some form of reaction and it was always assumed that it was because she was allergic.

IF you are interested,here is more information. (Again, no alliance, just my own info that we use.)

First, this is the chart. (Our son lacks both 2C9 and 2D6 enzymes.)

http://medicine.iupui.edu/clinpharm/ddis/main-table/

Here is a bit more info:

http://www.mayoclinic.org/tests-procedures/cyp450-test/basics/definition/prc-20013543

I know this was long.
I hope it helps someone. I truly believe that he day is coming when we will all be routinely tested for these sort of things to determine how to best treat diseases.

Dear Bedrestmom,


First of all, I applaud you for taking such a good care of your son and I wish him a speedy recovery. Also, more power and wisdom to you on your journey to find a cure for your precious son.
I totally agree with you that the majority of the MD's do not have a clue on the latest medical science and discoveries. They don't have a clue that there is new treatment tools available to their pt's. Some of them are so set in their old school ways of treating their pt's and totally ignoring the fact that the medicine is going forward in to a new era.
Personalized medicine is the future of the health care. It saves lives, drug interactions, medical mistakes, better treatment outcomes and definitely saves lots of tax payers money.
I do recommend highly for each individual to be more proactive in their health and do their own homework on the latest treatment options by going to reputable research medical centers, teaching universities and government web sites.
Continued success and good luck to you!
Sincerely,
Susan



bedrestmom said:

I am so glad that more attention is being paid to this.
First off, I am just a teacher. NO affiliation to any clinic, university, or lab. But I have a son with Tourette Syndrome, Chiari Malformation, Intracranial Hypertension, a shunt, and chronic pain.
He also has multiple medication sensitivities. We thought he just had an ever-growing list of medications that he was "allergic" to. We had multiple trips to the ER for serious reactions.
Finally, his wise neurologist suggested we have him tested for medication sensitivity.
Wow. It changed our lives.
The test is for the Cytochrome P450 set of liver enzymes that are necessary for breaking down medications.
Scientists are constantly finding new enzymes, as well.

A person who manufactures too much of an enzyme will metabolize a medication very quickly. This could be explained by people who say that pain medication does "nothing" for them, or that the effects only last for about an hour. It's because they are metabolizing too quickly.

However, in the case of my son, he lacks three key enzymes that are known to break down certain drugs, including some pain killers, Risperidol (which he was given for his Tourette's) and several others.

So what happens is that in his body a lack of enzymes means the medication cannot be broken down. It appears as though he is having an allergic reaction when he really just has a toxic level of medication in his body.
Since we had this test done, he has never had another "allergic" reaction to medications!
He has a lot of serious medical issues, so I never travel without my handy P450 chart, which shows all the meds he simply cannot metabolize.

Now, here is the scary part: most physicians have never heard of this! Hospital pharmacists are very helpful, but other physicians have never heard of this and so therefore look at me as if I am crazy when I tell them that he can't metabolize certain drugs! I was even shocked to find out that not all residents were taught this in med school!
Thankfully, the hospital where he gets his care is aware of this and very good about checking "the list" before prescribing something.

I truly think this is more common than we realize. We all know people who have bizarre reactions to medications. My own grandmother could take nothing without having some form of reaction and it was always assumed that it was because she was allergic.

IF you are interested,here is more information. (Again, no alliance, just my own info that we use.)

First, this is the chart. (Our son lacks both 2C9 and 2D6 enzymes.)

http://medicine.iupui.edu/clinpharm/ddis/main-table/

Here is a bit more info:

http://www.mayoclinic.org/tests-procedures/cyp450-test/basics/defin...

I know this was long.
I hope it helps someone. I truly believe that he day is coming when we will all be routinely tested for these sort of things to determine how to best treat diseases.

Thank you, Susan.

Sometimes the parenting journey takes us to very unexpected destinations.

Blessings to you.