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Research Shows Ultrarapid Metabolizers of CYP2D6 Face Increased Risk of Hospitalization

By | Adverse Drug Reactions, Pharmacogenetic Testing, Pharmacogenomics, Precision Medicine, Provider | No Comments

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.”

pgx testing

Researchers at Vanderbilt University Call for Pre-emptive Genetic Testing in CVD Patients

By | Other, Pharmacogenetic Testing, Pharmacogenomics, Precision Medicine, Provider, Statins | No Comments

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 side effects

CPIC Issues 2017 Guidelines for Optimal Warfarin Dosing

By | Pharmacogenomics, Precision Medicine, Provider | No Comments

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.”


Cancer Pharmacogenomics: Review of Implementation Challenges and Patient Perspectives

By | Pharmacogenomics, Provider | No Comments

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.

Dangerous Drug Combinations are Missed by Half of Pharmacies

By | Adverse Drug Reactions, PGx in the News, Provider | No Comments

A recent article in the Chicago Tribune “Pharmacies miss half of dangerous drug combinations” discussed their two year study on over 250 pharmacies to determine how often stores would dispense dangerous drug pairs without warning patients. The results showed that more than 50% of pharmacies prescribed dangerous combinations without notifying the patients.
According to the article, speed of medication delivery, fatigue and competition are major influences. For instance, one pharmacist said she filled out prescriptions every two seconds, showing pharmacists succumb to the demands of the customer’s, drug warnings are ignored and the prescribers make errors due to fatigue.
In response to the Tribune research, CVS, Walgreens and Wal-Mart each stated that they would take “significant steps to improve patient safety at its stores nationwide.” Combined, the initiative would impact 22,000 drugstores nationwide and involve additional training for 123,000 pharmacists and technicians, according to the article.
The “warning light fatigue” has implications for drug-gene interactions – the take away is “you can’t exclusively rely on your physician or your pharmacist.” As we look ahead, the Rxight genetic testing solutions and how our customers engage with them, may be more important than we ever considered.

South Dakota Health System Drives Costs Down with PGx Testing

By | PGx in the News, Provider | No Comments

Pharmacogenetic testing is becoming the new frontier in precision medication. It provides critical guidance to physicians when determining the most appropriate therapeutics and optimal dose of medications tailored to each individual patient. Despite the clear benefits of PGx, few health systems have implemented it as there are quite a few hurdles to overcome: convincing insurers to cover the cost, providing rapid turnaround of test results, and collecting more data on the cost effectiveness of a PGx testing program.


Avera Health, a health system in Sioux Falls, South Dakota, is finding solution to such challenges. Avera Health’s largest hospital, 545-bed Avera McKennan Hospital and University Health Center in Sioux Falls, performs pharmacogenomic testing on surgery patients to determine how well these patients metabolize opioid pain medications, according to TDR Insider
“Pharmacogenomic Testing a Success at South Dakota Health System” (Jan 2017).


For rapid turnaround of the testing, the lab performs genotyping and enters the data into the EMR so that the physician knows how the patient metabolizes medications in a timely manner. Such quick results lead to patients having the appropriate medication within 24 hours and to more data which can be presented to insurers. Our administration recognized the potential of pharmacogenomic testing to improve patient care and to reduce costs through quicker treatment success and fewer adverse effects,” said Krista Bohlen, PharmD, the Director of Personalized Pharmaceutical Medicine at the Avera Institute for Human Genetics. our laboratory reports the test results, then physicians follow the dosing guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy,” Bohlen said. “In addition to these guidelines, we also evaluate primary literature.”








CYP2D6 Polymorphisms and Risperidone Treatment

CYP2D6 Polymorphisms and their Influence on Risperidone Treatment

By | Antipsychotics, Provider, Psychiatric Medications | No Comments

The clinical utility of genomic profiling in risperidone pharmacotherapy was discussed in Pharmacogenomics and Personalized Medicine “CYP2D6 polymorphisms and their influence on risperidone treatment” (Dec 2016). Risperidone (Risperidal) is an atypical antipsychotic (AAP) drug that is indicated for the treatment of autism, schizophrenia, and acute bipolar mania. It exerts its pharmacologic effects by binding to and inhibiting serotonin and dopamine receptors.


Risperidone is metabolized by hepatic metabolism via the CYP2D6 enzymatic pathway to its major active metabolite 9-hydroxyrisperidone and therapeutic response and likelihood of risperidone side effects based on plasma concentrations of risperidone and its metabolite. According to the investigators, several studies suggested that CYP2D6 polymorphisms were associated with these plasma concentration. Hence, CYP2D6 poor metabolizers showed more serious adverse events such as weight gain and prolactin than other predicted phenotype groups.


According to researchers, “As the knowledge of pharmacogenomics of CYP2D6 in risperidone treatment is increasing, it can be used for the development of personalized medication in term of genetic-based dose recommendation,” and advocated for future research into genetic-based risperidone treatment.







Plavix and genetic testing

University of Maryland Offers Genetic Testing as Standard of Care for Heart Stent Patients

By | PGx in the News, Provider | No Comments

Plavix (clopidogrel) is a blood thinner that is used to reduce the risk of heart disease and stroke.  It is a popular drug and is considered to be safe for most patients. However, there is real risk that patient may not be able to metabolize the drug appropriately, and thus receive no benefit from the medication – or, conversely – suffer adverse reactions to Plavix such as statin myopathy, according to researchers at the University of Maryland, as reported in November at the American Heart Association’s Scientific Sessions in New Orleans.


In response to these findings, the University of Maryland Medical Center has launched a program to conduct genetic tests for the liver enzyme CYP2C19 before prescribing Plavix and other medications to patients who have received a heart stent. The enzyme affects the patient’s ability to metabolize the drug. Sixty percent of the patients with reduced CYP2C19 function were given an alternative medication. The result was reduction of the percentage of heart attacks and death by nearly half compared with those who continued taking clopidogrel.


Alternative medications, while not statistically as effective at Plavix, were found to be adequate replacements, according to the UMMC researchers.  Thus, the trial and error process was reduced and patient receive the appropriate medication early in treatment.


“This is a true personalized medicine initiative,” says Mark R. Vesely, MD, an associate professor of medicine at UM SOM and an interventional cardiologist at UMMC who was a co-investigator of the study. “The test provides the ability to optimize therapy for a specific patient by helping us tailor our treatment based on the patient’s unique genetic profile.”


Source:  University of Maryland Medical Center “University of Maryland Medical Center Offers Genetic Testing as Standard of Care to Help Improve Outcomes for Heart Stent Patients” (January 2017).

tegretol side effects

Study Details Genetic Influence on Carbamazepine Adverse Reactions

By | Adverse Drug Reactions, Drug Metabolism, Provider | No Comments

Carbamazepine (branded as Tegretol) is an anticonvulsant that is used to treat seizures and bipolar disorder among other psychiatric conditions. As effective as the drug is at treating such diseases, patients can suffer from potentially fatal or disfiguring adverse reactions.
The primary genetic culprit behind such severe reactions is HLA-B*15:02, according to a recent University of Liverpool study. The findings were published in Pharmacogenomics and Personalized Medicine “The HLA-A*31:01 allele: influence on carbamazepine treatment,” (November 2016).

“There is no doubt that there is an association between HLA-A*31:01 and CBZ hypersensitivity, in particular to HSS, in many different ethnic groups,” the authors state, noting that ethnic groups such as Asian population are at greater risk.

What is the HLA-B*15:02 Allele?


HLA-B*15:02 is an human leukocyte antigen (HLA) allele which is involved in the body’s inflammation response, as encoded by white cells (leukocytes). Specifically, the HLA s is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. The proteins encoded by certain genes are also known as antigens.


Adverse Reactions in Genetically Susceptible Patients


Severe adverse reactions can occur in genetically susceptible patients who are administered carbamazepine. Side effects include: toxic epidermal necrolysis (TEN), Stevens–Johnson syndrome (SJS), hypersensitivity syndrome (HSS) and milder reactions, such as maculopapular exanthema (MPE). Such reactions can be severe, life-threatening and disfiguring, the study noted.

“The mortality rate of TEN at 1 year is 34%, and in pediatric patients who survived acute TEN, all patients suffered with long-term complications, which included scarring, visual loss and chronic kidney disease,” according to the article.

Researchers Call for Pharmacogenetic Screening

The study identifies the challenges in applying pharmacogenetic screening for HLA-A*31:01 and proposals for overcoming these barriers. Specifically, the study notes that currently the carbamazepine summary of product characteristics approved by the European Medicines Agency for testing for HLA alleles mandates testing for HLA-B*15:02 before the use of CBZ in certain ethnic groups, but mentions HLA-A*31:01 for information only.
“At present, there is a disconnect between health technology assessment and regulatory advice, the authors state. “For precision medicine to succeed, we need to look at all forms of evidence, rather than relying on the usual paradigm of prospective studies or randomized trials.”

Understand Your Risks with the Rxight® Genetic Test

MD Labs’ Rxight® pharmacogenetic testing is based on the analysis of a comprehensive genetic panel identify whether genetic variants are present that put patients at risk for side effects or medication inefficacy. Over 200 medications across over 50 clinically significant pharmacological classes are tested ( including carbamazepine). All that is required is a simple cheek swab which is sent to our lab for analysis. The results, which are reviewed in detail with patients, are designed to guide prescribers in devising treatment plans that are based in the patient’s unique genotype.








PGx as Applied to ACS Protocol

PGx as Applied to ACS Protocol: Maximizing CMS Incentive Payments to Hospitals

By | CMS Cardiac Bundle, PGx in the News, Provider | No Comments

Anti-platelet pharmacotherapy is an established standard of care for Acute Coronary Syndrome (ACS) to reduce thrombotic risk. Incorporating pharmacogenetic testing and pharmacist engagement into the prescribing protocol allows the provider to understand the patient’s genetic phenotype to help determine whether the patient will achieve the optimal therapeutic outcome – and thus mitigate potentially serious adverse effects or sub-optimal treatment response.

Using PGx/ACS Protocol to Enhance Quality-Based Payments

The new PGx/ACS Protocol can help maximize CMS quality-based incentive payments. As discussed in Becker’s Hospital Review “How managing medications based on genetics can enhance quality-based payments” (January 17 2017), pharmacogenetic testing can reduce drug-related complications and readmission rates, thus sparing added costs to hospitals and providers.
A recent report out of the University of Illinois Hospital & Health Sciences System demonstrated that PGx reduced 90-Day ER and Hospital Readmission Rates by 68% leading to $2,043 savings per patient and almost $600K overall savings to UIC. This becomes even more important as the new CMS Cardiac Bundle takes effect this coming July.

Contact MD Labs for Information on the PGx/ACS Protocol and
its Turnkey PGx Testing Program

Contact MD Labs for details on the PGx/ACS Protocol and how to implement it with the Rxight® PGx program. A cornerstone of MD Labs’ Rxight® program is incorporating PGx trained and certified pharmacist as part of the protocol, as pharmacist involvement in patient care is proven to help reduce readmission rates.
MD Labs’ Rxight® Program provides turnkey implementation and includes pharmacist training in PGx and certification to conduct PGx consultations. Additionally, the Rxight® program is integrated within the hospital lab offerings for establishing collection procedures. DNA test kits are provided by MD Labs, and results are accessible via online provider and patient portals.
Assess your hospital’s cost saving opportunity by calculating the 90-day hospital readmission costs due to drug-related complications (clopidogrel and coumadin), over the last 3 years. Call MD Labs at 1-888-888-1932, or email info@Rxight.com to get started. Rxight.com