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.
Antiplatelet agents combined with aspirin have been shown to play a significant role in mitigating the effects of coronary disease, and ample research has found that distinct genetic determine patients’ response to clinically significant antiplatelet agents.
Platelets play a decisive role during the formation of an initial hemostatic plug through their intricate response to injury. When inappropriately activated, platelets contribute to pathological thrombus formation. Arterial thrombus formation can then lead to tissue ischemia causing potentially fatal coronary and cerebrovascular events.
Interindividual Genetic Variation Impacts Aspirin Antiplatelet Efficacy
Aspirin is regarded as “the cornerstone for secondary cardiovascular prevention,” the efficacy of which has long been established. as noted in Current Pharmaceutical Design, “Pharmacogenetics of the Antiplatelet Effect of Aspirin” (2012).
The researchers aver that there is considerable interindividual variation in response to aspirin, thus reducing its efficacy in treating heart disease in some patients.
P1A2 and P2Y1 Association with Decreased Aspirin Antiplatelet Efficacy
Specifically, the review conducted by Current Pharmaceutical Design examined polymorphisms of genes that contributed highly to antiplatelet responses. These were P1A2 from glycoprotein GP IIb/IIIa, and the P2Y1 polymorphism from AD receptor (ADP) genes.
P1A2 was characterized as having an association with coronary thrombus formation. One study showed P1A2 allele was related with a shorter baseline bleeding time in comparison to a wild type allele. After measuring bleeding after aspirin ingestion, there was a a reduced antiplatelet effect.
Another study supported this finding by discovering an enhanced thrombin formation in P1A2 carriers compared to P1A1/A1 homozygotes before and after aspirin ingestion. The review concluded that P1/A2 polymorphism is a prothrombotic platelet phenotype responding inadequately to aspirin.
Polymorphism P2Y1 was utilized in an arachidonic acid-induced optical platelet aggregometry to assess its antiplatelet effect of aspirin. The results showed that the T allele of the C893T P2Y1 polymorphism was substantially linked with a decreased antiplatelet effect of aspirin.
CYP2C19 Mediates Clopidogrel Non-Response
Evidence for association of CYP2C19 with clopidogrel response was investigated in the Journal of Human Genetics “Pharmacogenomics of Anti-Platelet Therapy: How Much Evidence is Enough for Clinical Implementation?” (June 2013).
The study established CYP2C19 as a genetic factor contributing to the creation of the active metabolite of clopidogrel. A corresponding analysis detailing the associations of CYP2C19 alleles and increasing residual on-treatment platelet reactivity corroborated this finding. The study concluded that patients with even one reduced function of CYP2C19 and taking clopidogrel as treatment for percutaneous coronary intervention may be “associated with increased risk of major adverse cardiovascular events as a consequence of aspirin antiplatelet inefficacy.
The International Journal of Environmental Research and Public Health “Pharmacokinetic and Pharmacodynamics Responses to Clopidogrel” (February 2017) also reviewed the connection between CYP2C19 and clopidogrel. The review was based on the authors’ argument that genetic polymorphisms impact the absorbtion and metabolism of clopidogrel and that the P2Y12 receptor may interfere with its antiplatelet activity.
In one meta-analysis, it was found there was a critical relation between CYPC219 loss-of-function in diverse patients with frequent cardiovascular events. In another meta-analysis, CYPC219 was identified as having a having a crucial part in reducing the active metabolite of clopidogrel.
CYP3A4/5 Mediates Clopidogrel Non-Response
In addition to analyzing clopidogrel, the review also analyzed CYP3A4/5. The authors found that the CYP3A5*3 allele has an influence on clopidogrel metabolism because of its possible dependence on CYP2C19 and CYP3A4 inhibitors. In the study, the patients with a CYP3A5*3/3 genotype displayed enhanced platelet reactivity compared to those with a CYP3A5*1 allele in CYP2C19 poor metabolizers. An additional study reported CYP3A5*3 on clopidogrel response is prominently in patients with the CYP2C19 loss-of-function.
Benefits of Individualizing Antiplatelet Therapy with Pharmacogenetic Testing
Research has been conclusive in identifying potential antiplatelet pharmacogenetic applications pointing to effective individualized treatments, according to the studies.
The review by the International Journal of Environmental Research and Public Health asserted there is an “inter-individual variability” in clopidogrel’s antiplatelet effects. They concluded inadequate platelet responsiveness to clopidogrel has a role in accumulating the risk of cardiovascular events, and therefore increasing drug dosage or switching to alternative drug medications may be more beneficial for patients. Similarly, the review published in Current Pharmaceutical Design concludes by recommending utilization of antiplatelet pharmacogenetics in clinical practice. “The promise of pharmacogenetics lies in the prospect of improving treatment efficacy and safety.”
Pharmacogenetic testing refers to a type of genetic test to predict a patient’s likelihood to experience an adverse event or not respond to a given drug. Despite revision to several labels of commonly prescribed drugs regarding the impact of genetic variation, the use of this testing has been limited in many settings due to a number of factors. As a pillar of the personalized medicine movement, pharmacogenetics for physicians is anticipated to be important across all medical specialties particularly with the increasing popularity of concierge medicine.
Several pharmacogenetic tests have been developed, based on the data from numerous genomic studies to correlate genetic variation with variable drug response. A handful of these tests, both protein- and DNA-based, have subsequently been approved for in vitro diagnostic testing.
Pharmacogenetic testing is currently available for a wide range of health problems including cardiovascular disease, cancer, diabetes, autoimmune disorders, mental health disorders and infectious diseases. PGx contributes important information to the field of precision medicine by clarifying appropriate treatments for specific disease subtypes. Tangible benefits to patients including improved outcomes and reduced total health care costs have been observed. Coverage by insurers is a critical step in achieving widespread adoption of pharmacogenetic testing. The acceleration of adoption of precision medicine in general and for pharmacogenetic testing in particular will be determined by how quickly robust evidence can be accumulated that shows a return on investment for payers in terms of real dollars, for clinicians in terms of patient clinical responses, and for patients in terms of economic, health and quality of life outcomes.
In 2005, the FDA approved the first pharmacogenetic test based on microarray technology for genotyping 27 alleles in CYP2D6 and three alleles in CYP2C19 genes associated with different metabolizing phenotypes. Today, pharmacogenetic testing has become an integral part of the treatment of breast cancer with trastuzumab. Overexpression of the HER2 oncogene is correlated with a poor prognosis, increased tumor formation and metastasis, as well as resistance to chemotherapeutic agents. HER2 testing predetermines patients who overexpress HER2 and who will respond to trastuzumab.
With rapid advances in genomic technology, costs of pharmacogenetic testing have decreased in recent years. In addition to improved treatment outcomes, genetic testing can reduce high costs related to treatment failures and severe adverse events.
Cytochrome P450s (sometimes referred to as CYPs) are proteins involved in almost 75% of phase I drug metabolism. They are part of the heme cofactor superfamily and therefore hemoproteins. The active site of the P450 enzyme contains a heme-iron center. Most P450 enzymes will require a separate protein to deliver one of more electrons to reduce the heme-iron centre. They are predominantly involved in Phase I metabolism. The P450 enzymes are present in hundreds of isoforms in the human body. Different isoforms of P450 results in different reactions catalyzed and different molecules regulating that catalysis.
As P450’s are so important to drug metabolism, understanding genetic abnormalities in these enzymes can be a real help when it comes to pharmacotherapy. For instance, knowing a patient has a polymorphism of CYP2D6 that results in rapid metabolism of codeine will indicate that this patient will not see much pain relief from the drug.
The Rxight® genetic test covers a number of P450 enzymes. These are:
Within these, CYP2C9, CYP2C19 and CYP2D6 are of significant importance, accounting for almost 35% of all phase I metabolism of clinically used drugs.
The P450 enzyme CYP2C9 is of significance in the breakdown of the commonly used anticoagulant warfarin. Polymorphisms in CYP2C9 account for a significant proportion of variation in dose requirements.
CYP2C19 is required for metabolism of 10% of medicines used today. It metabolizes a number of anti-ulcer drugs including the proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, etc.). It has other clinically important polymorphisms regarding platelet drugs such as clopidogrel. These mutations can result in excessive anticoagulation and increase the risk of bleeds, or can result in little to no response from the drug.
CYP2D6 can result in the reactions discussed above relating to the opiate codeine, but it is also responsible for metabolizing a number of tricyclic antidepressants. Some polymorphisms can result in no response from the drug, or can result in drug reactions (e.g., serotonin syndrome).
What is Individualized Medicine?
Individualized medicine is a term often used interchangeably with personalized medicine, stratified medicine and precision medicine (although some argue there are slight differences between each term). Broadly speaking, individualized medicine refers to the practice of tailored treatments based on predicted outcomes. This means that physicians and pharmacists identify how they predict a patient will react to a drug or treatment before administering it and choose the medication with the best predicted outcome.
Over the past 50 years, there has been a growing “one size fits all” attitude to practice in medicine. Diseases are treated as happening to a patient, and each disease has a specific treatment. But this overlooks the variability in individuals, and there has been a recent push back towards putting individual patients at the centre of care. This was highlighted in 2015, when President Barack Obama announced The Precision Medicine Initiative. This initiative hopes to push individualized medicine into the mainstream, powering $215 million of research into pioneering new research and technologies.
How will Individualized medicine be achieved?
Individualized medicine relies on the principle of inter-person variability. Each patient is different, and as such should be treated differently. Each patient has a genetic code, which is different in every individual and defines everything from what they look like to how they metabolize drugs. It has long been noted that many patients react differently to the same drug. A number of factors can affect this although the major one is the patient’s genetics.
In 1954 the field of Pharmacogenetics was born when two German physicians noticed variable reactions to the anti-TB drug Isoniazid. This difference was caused by the different genetics of patients. Each gene has variations, or polymorphisms, between individuals that affect the function of the protein that is built from that genetic code. In some individuals, these polymorphisms mean they metabolize certain drugs slowly or not at all. An example of this is the gene CYP2D6, the protein to which it makes turns codeine into its active form morphine. Some individuals metabolize codeine slowly or not at all, meaning they never produce the active analgesic (anti pain medication) morphine. These patients exhibit no pain relief from codeine.
This simple example of codeine metabolism can be extrapolated to hundreds of drugs and genes. This is what MD Labs achieves with
Rxight®. We sequence many genes and identify polymorphisms that are likely to affect the action of over 200 drugs. From this physicians and pharmacists can produce a picture of how a patient is likely to respond to pharmacotherapy – preferably before treatment begins.