Rxight Pharmacogenetics has become an affiliate member of the NIH-funded effort, IGNITE (Implementing GeNomics In pracTicE). IGNITE is a network dedicated to supporting and advancing the use of genetic information across clinical and diverse healthcare settings. It is comprised of a series of projects aiming to enhance translation of validated actionable genomic information into clinical settings and decision making, and includes educational initiatives for patients and providers. IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice, and Rxight Pharmacogenetics is proud to be a member of this step forward in clinical care.
Medications are central to the treatment of schizophrenia and a number of drugs are used to treat this serious mental condition. Schizophrenia is a long-term mental disorder marked by psychosis- a breakdown in the relation between thought, emotion, and behavior, leading to errors in perception, inappropriate actions and feelings, withdrawal from reality, and a sense of mental fragmentation.
Most patients are now treated with antipsychotics that are thought to control symptoms through the brain chemical, dopamine. There are two types of antipsychotics used: first generation and second generation.
First Generation Antipsychotics
The first generation antipsychotics have more serious side effects and are used only when necessary. They include haloperidol (Haldol), chlorpromazine (Thorazine), and Fluphenazine (Prolixin). Side effects of first-generation antipsychotics include extrapyramidal side effects which is marked by rigidity, bradykinesia, dystonias, tremor, and akathisia. Tardive dyskinesia (TD)— a disorder marked by permanent involuntary movements in the limbs and face such as grimacing and lip-smacking – is another adverse effect that can occur with first-generation antipsychotics. Additionally. first-generation antipsychotics are known to cause cardiac rhythm abnormalities.
Second Generation Antipsychotics and Side Effects
The newer second generation antipsychotics have less side effects than the older drugs, and are preferred for treatment of schizophrenia. They include: aripiprazole (Abilify), asenapine (Saphris), brexipiprazole (Rexulti), clozapine (Clozaril), Iloperidone (Fanapt), Lurasidone (Latuda), Olanzapine (Zyprexa), Paliperidone (Invega), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon).
Abilify side effects include akathisia (agitation), restlessness, insomnia, constipation, fatigue and blurred vision. Most of the second-generation antipsychotics have similar side effects, as they are similar chemically. Geodon is one of the newer antipsychotics with extra-pyramidal side effects reported (drug induced movement disorders).
During initial phases of treatment with the second generation antipsychotics patients may experience side effects such as dry mouth, drowsiness, restlessness, muscle spasms, tremor or blurring of vision. The second generation antipsychotics have a much lower risk of tardive dyskinesia, a serious side effect of the older antipsychotics. It is possible to lessen side effects by either lowering the dose or by changing medications.
Patients and physicians often work together to find a dose that results in the fewest side effects. Patients will often change medications if the side effects are severe and side effects lessen over time. One way to potentially avoid side effects for new medications and for newly prescribed schizophrenia medications is to have your drug metabolism genes tested. After the human genome was sequenced back in 2003, genome wide association studies showed that there is variation among the population in the genes that process medications. As a result, if there’s a drug-processing gene with variation, it may have trouble processing medications that are metabolized by that gene product.
Know Your Risks with the Rxight® DNA Test
The most state-of-the-art way to determine genetic variations is with the Rxight® pharmacogenetics test from MD Labs. This advance in pharmacogenetics means that a physician can determine beforehand what drugs may be safe to take and what drugs to avoid or require different doses than recommended. All that is required is a prescription from a physician and a cheek swab at a participating pharmacy.
You could benefit from this advance in precision medicine with the knowledge of your gene variations with your physician or other healthcare services. The Rxight® pharmacogenetics test determines your genetic susceptibilities for over 200 drugs on the market. You could also benefit from knowing how you might respond to drugs you may have to take in the future. Most importantly, you could get information that may change your current dosing and medication for fewer harmful side effects from your antipsychotic medication.
Opioids are the most potent analgesics and are used to treat severe pain, specifically pain associated with cancer – a significant factor in reducing quality of life and clinical outcomes in such patients as detailed in Cancer Control “Clinical Implications of Opioid Pharmacogenomics in Patients with Cancer” (October 2015).
Inter-individual Differences in Genetically Modulated Opioid Response
The study reviewed clinical studies involving the pharmacodynamics and pharmacokinetics of opioids. It examined the opioid agents morphine, codeine, tramadol, oxycodone, fentanyl, and hydrocodone and the relationship to single nucleotide polymorphisms (SNPs): OPRM1, COMT (specifically COMT Val Met), CYP2D6, CYP3A4/5, and ABCB1, which the study claimed are responsible for the inter-individual differences in opioid response.
The authors specifically found that OPRM1, COMT Val Met, and ABCB1 are most strongly correlated with morphine response. One study combined OPRM1 and ABCB1 and found that patients with both of these genetic variants were the best responders as indicated in patients’ measures of pain intensity. In another study, patients with OPRM1 and COMT Val Met needed the lowest morphine dose compared to other genotypes. All three together demonstrated no difference in morphine dose requirements.
CYP2D6 Variants Correlate with Drug Efficacy
Similarly, the presence of CYP2D6 variants correlated positively with variations in codeine and tramadol efficacy. CYP2D6 is responsible in converting the analgesic properties of codeine and tramadol. In studies investigating codeine pharmacotherapy in cancer patients, analgesic differences and adverse effects were found for CYP2D6 poor, intermediate, and extensive metabolizers.
The authors concluded CYP2D6 testing helps in finding which patients respond positively to codeine. Studies with tramadol focusing on non-cancer pain populations identified CYP2D6 poor metabolizers as having a decreased analgesic response compared to extensive metabolizers. However, the authors noted there has been no specific study relating to tramadol’s analgesic efficacy in cancer populations, arguing tramadol will likely have decreased clinical benefit in patients who are poor CYP2D6 metabolizers.
Call for Preemptive Genotyping in Clinical Practice
The authors assert that these findings “suggest genotyping patients for some of these genetic variants may help predict responses to pain treatments with good rates of sensitivity and specificity and with greater benefits for patients and decreased health care utilization.” Furthermore, the authors assert that utilizing pharmacogenomics data combined with a preemptive genotyping be a “key element” in guiding treatment decisions for cancer patients.
Statin treatment in women without cardiovascular disease is controversial. Research has found that for women with elevated LDL levels as their only cardiovascular risk factor, the benefit of lowering LDL cholesterol with a statin drug might not outweigh the risks.
According to an article in Circulation “Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia” (March 2010) many women take statins and suffer side effects similar to those experienced by men. Statin side effects range from mild to severe and include liver damage, myopathy, and behavioral and cognitive problems.
Revised Treatment Guidelines Push for Increasing Statin Use
Treatment guidelines issued in 2014 in the New England Journal of Medicine suggest that up to 13 million more adults should be taking statins. The revised guidelines changed the focus from specific cholesterol levels to a wider assessment of heart attack and stroke risk.
Opponents Claim Too Many Women Prescribed Statins
Not everyone agrees with these new treatment guidelines, as reported in the New York Times, also in 2014: “Among men 60 to 75, the percentage would jump to 87 percent from 30 percent; among older women, it would increase to 54 percent from 21 percent.” In that New York Times article, the chief of cardiovascular medicine at the Cleveland Clinic said the report confirmed his concerns that the new guidelines “don’t target the right patients for treatment.” He faulted the study for not taking into account the family history of cardiovascular disease: “Should so many women be taking statins? Far too many healthy women are taking statins, they say, though some research indicates the drugs will do them little good and may be more likely to cause serious side effects in women.”
Women Found to Suffer More Side Effects from Statins Than Men
These studies highlight the fact that fewer women take statins than men, and that women suffer more side effects from statins than men. Although women represent about half the population, they are enormously under-represented in clinical trials of statins. It follows that the evidence on the benefits and risks for women is scarce. In one of the studies American Journal of Cardiology “Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)” (Jan 2006), there was no significant reduction in heart attacks, strokes and deaths among the women while the male participants on statins had fewer heart attacks and strokes.
Weigh the Risks and Benefits with Genetic Testing
Some side effects of statins and other drugs may be reduced by either altering the dose or by changing the particular statin prescribed. Side effects in general may be reduced by taking into account the variation in your drug metabolism genes. The study of variation in the drug metabolism genes defines the field of Pharmacogenetics. This advanced genomics field emerged after the human genome was sequenced and has become an important field of its own.
Rxight® Pharmacogenetic Testing for Statin Side Effects
Pharmacogenetics research showed there is variation in the genes that are responsible for processing drugs. That means that if a particular gene has variations it may result in a gene product (protein or enzyme) that is non-functional or has reduced function. This altered function, which can sometimes mean an inability to process a medication or a reduced ability to process a medication, may result in adverse side effects. Side effects may be lessened by avoiding those drugs that you don’t have the ability to process normally.
Once you and your physSician have these results you can use them for your lifetime. The results allow your physician to interpret your ability to metabolize over 200 drugs on the market. Your physician will then have at hand the predictive ability to prescribe drugs that are safer for you and to possibly avoid side effects with any new medication. With the Rxight® pharmacogenetic test from MD Labs you can bring precision medicine home to your personalized medical care.
The cytochrome P450 2D6 (CYP2D6) hepatic enzyme is responsible for the metabolism a wide range of medications and other substances. For example, opioids such as codeine, morphine and tramadol are activated by CYP2D6, while several classes of antidepressants and antipsychotics are in made inactive by the CYP2D6 enzyme. While it has been shown extensively that variation within the genes controlling drug metabolism has been associated with toxicity/adverse drug reactions or conversely drug inefficacy, there is a dearth of data on the adverse health outcomes of the potential impact of extreme metabolism phenotypes (ultrarapid / poor metabolism of CYP2D6) on hospitalization and emergency department (ER) visits.
A recent study published in Pharmacogenomics and Personalized Medicine “Increased risk of hospitalization for ultrarapid metabolizers of cytochrome P450 2D6” (Jun 2016) found a patient’s CYP2D6 phenotype has a statistically significant impact on the rate of hospitalization from adverse drug effects for ultra-rapid metabolizers in comparison to extensive metabolizers. The hypothesis was that participants with ultra-rapid and poor metabolism would have higher rates of hospitalization.
The investigators examined hospital records over a 9-year period, employed data from the Mayo Clinic Biobank on patients enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment (RIGHT) protocol, which sequenced 86 pharmacogenomics genes for clinical use. For the study, a cohort of 929 adult patients underwent CYP2D6 testing. CYP2D6 clinical phenotypes ranged from ultrarapid to poor metabolizer, with extensive metabolizer being the reference group. There was no statistically significant difference between other CYP2D6 phenotypes and controls.
“Precision medicine within pharmacogenomics can be used to predict adverse health outcomes such as hospitalization,” the study’s authors concluded. “There may be clinical utility in pre-emptively genotyping patients to decrease health care use.”
Cancer and cardiac patients are typically prescribed multiple medications due to the severity and clinical complexity of their illness. It has been proposed in numerous studies citing relevant data on statistically significant adverse medication reactions in this population that pharmacogenetic testing should be conducted pre-emptively on such groups to prevent adverse clinical outcomes.
Researchers at Vanderbilt University Medical Center’s Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT) investigated gene variants that were deemed clinically actionable based on institutionally approved clinical decision support advisors for five common DGIs (drug-gene interactions) in a clinical group of 10,044 cardiovascular disease (CVD) patients, as detailed in a January 2017 article in Pharmacogenomics and Personalized Medicine “Prevalence of clinically actionable genotypes and medication exposure of older adults in the community.”
The study analyzed clinically actionable pharmacogenotypes for clopidogrel, warfarin, statins, thiopurines, and tacrolimus. The researchers reported that 91% of patients had at least one actionable gene and more than 5% of patients were at high risk of suffering strong adverse reactions. Similar studies corroborate the PREDICT researchers’ findings, according to the article.
Pre-emptive genetic testing should therefore be integrated into standard care models, the researchers concluded. Given the preponderance of data on DGIs such as these, the investigators called for prescribers to give greater consideration to the possibility of clinically relevant drug-gene interactions in the older adult group. “Our findings affirm that pre-emptive genotyping is likely to have strong potential to improve medication safety, efficacy, and health outcomes,” the article stated. “Further investigations correlating genotypes and medication exposures to adverse reactions and other outcomes in older people appear justified.”
Warfarin (brand name Coumadin) is the most commonly used anticoagulant medication worldwide. It achieves its desired results with great efficacy, but is also a reason why patients are frequently hospitalized for adverse drug reactions. This is due to drug-gene interactions, complicated by warfarin’s narrow therapeutic window.
To address the need for greater the CPIC (Clinical Pharmacogenetics Implementation Consortium) has updated its guidelines to determine optimal warfarin dosing a more effective manner through pharmacogenetic testing, as reported by PharmGKB (02/08/2017).
Specifically, the CPIC’s revised 2017 recommendations are specific to continental ancestry, and are based on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823. The CYP2C9 hepatic enzyme is one of the primary metabolizer of warfarin. Additional or lack of the sixty CYP2C9 alleles are associated with adverse drug reactions. Another factor of warfarin-gene interaction is VKORC1, which encodes the vitamin K epoxide reductase protein, the target enzyme of warfarin. Variants of this protein determine warfarin sensitivity. Genes CYP4F2 and CYP2C rs12777823, also greatly affect the patient’s response to the medication and susceptibility to adverse reactions to anticoagulants.
Warfarin dosing algorithms grounded in pharmacogenetics have been effective at determining appropriate treatment. According to the CPIC, “[i]ncorporation of genetic information has the potential to shorten the time to attain stable INR [international normalized ratio], increase the time within the therapeutic INR range, and reduce underdosing or overdosing during the initial treatment period.”
Scientists worldwide collaborated on the Human Genome Project between 1990 and 2003, resulting in the identification of approximately 25,000 human genes and the sequencing of roughly 3 billion DNA pairs. Sequencing the genome has provided medical science valuable information about the human body including heredity, evolution, the genetic basis of illnesses and the ways that drugs affect diseases.
Genetic testing in 2001 was a time-consuming, costly undertaking, as detailed in a March 2014 article in Nature “Technology: The $1,000 genome.” Costs for sequencing the human genome have fallen from about $10 million in 2001 to under $1,000 today. The efforts of the National Human Genome Research Institute to encourage research scientists and institutions to develop cost-effective sequencing platforms has paid off. As more is understood about human genetics, disease and treatment; testing is becoming more specialized and less expensive.
Types of Genetic Testing
According to Genome.gov, today, genetic testing is used by doctors, researchers and other medical professionals for a number of reasons:
- Genetic testing is used to evaluate an individual’s risk of developing and diagnosing a disease.
- Prenatal testing and to screen newborns for particular diseases and disorders.
- Used by forensic scientists for legal identification of an individual and as a way to determine paternity.
Pharmacogenetic testing examines the way genetic variants affect the assimilation to medicines. The testing can help clinicians select medicines that have are more beneficial to the patient and avoid drug reaction. Because pharmacogenetic testing identifies an individual’s genetic variants, testing with Rxight® to tailor drug therapy programs to treat specific diseases such as cancer, AIDS, heart disease and diabetes.
Methods of Testing
There are many DNA testing laboratories that provide an assortment of DNA tests to doctors, pharmacists, other specialists and the public. Early testing, called Sanger DNA sequencing, was a painstaking process that took several weeks to produce results. Depending on the type of test and the quality of the DNA sample, newer methodologies can now deliver highly accurate results in just a few days. The development of microarray technology allows analysis of multiple samples at one time, in contrast to earlier methods that allowed analysis of only one gene at a time, as described in American Laboratory “Multistranded, Alternative, and Helical Transitional DNA and RNA Microarrays: The Next Generation”” (March 2011).
Accuracy and Validity of Testing
The federal government regulates the safety and accuracy of genetic tests. The Clinical Laboratory Improvement Amendments require that laboratories be certified to perform specific types of DNA testing. CLIA is overseen by the Centers for Disease Control. MD Labs, certified by CLIA, uses state-of-the-art testing platforms such as UPLC-MS/MS to provide fast, reliable results for several types of molecular testing.
MD Labs operates Rxight pharmacogenetic testing, which provides information about genetic variants for more than 200 prescription medicines. Testing is simple. DNA samples are extracted from a cheek swab and sent to MD Labs for analysis. Patients receive a Personalized Medication Review that is interpreted by a pharmacist certified in pharmacogenetics. Keeping the report on file allows pharmacists and clinicians to select medications that are compatible with a patient’s genetic characteristics.
Cancer treatment has evolved in recent years from broader cyctotoxic chemotherapies to much more focused immunotherapies and combinations of both therapies. With the sequencing of the genome in 2003 to the discovery of cancer biomarkers in efforts such as The Cancer Genome Atlas, pharmacogenomics has significant potential to positively impact cancer care and precision medicine today.
An article in Pharmacogenomics and Personalized Medicine, “Cancer pharmacogenomics, challenges in implementation, and patient-focused perspectives” (Mar 2016) offers an update on cancer pharmacogenomics, and highlights the challenges in applying pharmacogenomics to the clinical setting – with a review of patient perspectives on these developments.
With the evolutions of cancer care comes an acceleration in drug advancement and approval and concomitant diagnostic assays – which the author state are “critical in identifying predictive biomarkers that allow for a personalized approach to therapy selection,” Pharmacogenetics provides the opportunity to stratify patients into those likely to respond or not respond to therapy, or those likely to experience or not experience toxicity, according to the review.
For example, one of the most serious types of skin cancers, metastatic melanoma, carries the mutation BRAF. Once the BRAF mutation is activated, tumor growth will likely occur.
Dihydropyrimidine dehydrogenase (DPD) is the enzyme responsible for the most of the metabolism of Fluorouracil (an immunosuppressive agent that is used to treat many cancers that is included on the Rxight® panel). Variants in DPD result in cancer treatment inefficiency or, conversely, lead to adverse reactions. Understanding the patient’s DPD and other cell mutations leads to better treatment and helps prevent therapy toxicity, according to the article.
Key factors in the integration of pharmacogenetic testing into routine clinical practice is physician acceptance but also patient adoption and understanding of the risks and benefits of PGx testing, according to the review, which calls for further patient education on the benefits of pharmacogenomics and genomics-based medicine in the future.
“As our knowledge of cancer at the molecular level continues to expand, clinicians must understand the therapeutic implications of these pathways and the challenges involved with clinical implementation of pharmacogenomics,” according to the report. Elucidating these genetic difference will lead to the development of better cancer therapies but a larger scale implementation will be more difficult. More data needs be available and hospitals need to have quick access to such information to implement genetic testing on a wide scale.
The complete DNA sequencing of the human genome has opened exciting new avenues of research to medical science. Medical researchers now use genetic information to diagnose, treat and prevent disease. An important discovery made during the Human Genome Project showed that genetic variants can affect the way medicines are assimilated, transported and eliminated by the body. The science of pharmacogenetics studies the way genes affect drug metabolism. Genetic testing is now recommended before prescribing many drugs and is required for several medications that are associated with severe side effects. Rxight® pharmacogenetic testing examines the genetic variants of a patient to assess how these genetic characteristics may influence a drug’s effectiveness or have the potential to cause adverse reactions.
DNA Sequencing and Pharmacogenetics
The Human Genome Project analyzed approximately 30,000 genes and the sequence of 3 billion base pairs of DNA. This DNA sequencing revealed that several genes directly influence the metabolism of drugs, control drug pathways and affect the therapeutic benefit that a medication delivers.
Physicians have long recognized that some patients do not get any benefit from a drug while other people may have negative responses. Although there are many reasons that influence the way an individual reacts to a medication, genetic variation is a known factor.
Pharmacogenetic testing by DNA sequencing companies analyzes genes that affect drug metabolism. MD Labs is certified by Clinical Laboratory Improvement Amendments, a regulatory arm of the Centers for Disease Control. Certification ensures that testing methods and procedures undertaken by MD Labs meet federal quality standards.
MD Labs provides pharmacogenetic testing to help physicians and patients make informed decisions about how specific medications may affect a patient’s response to a drug. The test analyzes 60 alleles on 18 genes associated with drug metabolism. The lab offers several secure ways to deliver results to patients, participating pharmacies and physicians.
MD Labs provides pharmacogenetic services in certified pharmacies. Rxight® certified pharmacists take a patient’s DNA sample from a cheek swab and send the sample to MD Labs. A Personalized Medication Review® detailing the results of the test, is included in the cost of testing. Certified Rxight® pharmacists interpret the PMR for each patient. This information can be kept on file to ensure that medications and dosages prescribed and dispensed are appropriate for the patient’s genetic characteristics.
Clinical Pharmacogenetics Implementation Consortium and DNA Sequencing Companies
The Clinical Pharmacogenetics Implementation Consortium provides detailed information to clinicians, researchers and sequencing companies throughout the world about current pharmacogenetic research, proper implementation of pharmacogenetic tests in the clinic and guidelines about how drug testing information can be used to enhance the outcomes of drug therapy. CPIC provides detailed information about known pharmacogenetic interactions of specific drugs, genes and alleles with links to research about gene-drug interactions and federal labeling guidelines.
CPIC members are from universities, research institutes, industry, hospitals and patient advocacy groups with credentials demonstrating clinical, industry or policy experience in pharmacogenetics. Matthew Rutledge, founder of MD Labs, is a member of CPIC.