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The Pharmacogenetics of Antiplatelet Agent: Meta-Analyses of Aspirin and Clopidogrel Loss-of-Function Alleles

By | Anticoagulants, Pharmacogenetic Testing, Provider | No Comments

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.”

The Prospect of Pharmacogenetics in Pediatrics

By | Opioids, Other, Pharmacogenetic Testing, Provider | No Comments

Pharmacogenetics of Opioids as a Potential Alternative in Pediatric Pain Management

 
Opioid and codeine treatment in pain management for children has been a primary concern in clinical settings, specifically for surgical pain management. The concerns are the adverse reactions caused by the opioids, such as respiratory depression. Current Opinion in Anesthesiology, “Codeine and Opioid Metabolism: Implications and Alternatives for Pediatric Pain Management” (2017), reviews how important clinical factors and genetic polymorphisms affect the metabolism of opioids after surgical operations.

 

Adverse Side Effects of Codeine

 
Codeine’s efficacy has been questioned in the pain management of children. Current Opinion in Anesthesiology identifies the adverse reactions of it. The prominent ones are respiratory depression, anoxic brain injuries, and even death occurring in children. With reported doses of codeine, significant respiratory depression was found in newborns in a report by Canadian Pharmacists Journal “Pain Management in Children: A Transition from Codeine to Morphine for Moderate to Severe Pain in Children” (2012).

 
Opioids in Pain Management

 
Opioids are the cornerstone of pain and chronic pain management. “Successful pain management provides adequate analgesia without excessive adverse reactions affirms Clinical Biochemistry “Pharmacogenetics of Chronic Pain Management” (2014). Drug metabolism and responses are influenced by numerous factors, including pharmacogenetics. Genetic variations contribute to the distinct inter individual responses to pain medications.

 
Involvement of CYP2D6 in Codeine

 
Those with two nonfunctional alleles of CYP2D6 are considered poor metabolizers. Extensive metabolizers have one or two effective CYP2D6 alleles and those with duplicated CYP2D6 alleles are ultra rapid metabolizers. Canadian Pharmacists Journal indicates the functions of CYP2D6 are similar in both children and adults.

 
The review also acknowledges the safety concerns of CYP2D6 ultra rapid metabolizers from several studies. One study demonstrated how a breastfed newborn infant died after his mother consumed Tylenol #3 for postpartum pain. Toxicology testing found the mother had abnormally high concentration levels of morphine in her breast milk. Genotype testing found the mother was an ultra rapid metabolizer of codeine. The study concluded since the mother was an ultra rapid metabolizer, higher than normal morphine levels crossed into the breast milk and resulted in the infant dying from morphine intoxication.

 
Another study found a two-year-old child who also died of morphine intoxication. The child was prescribed codeine in recommended dosages after having his tonsils removed. Genotype testing revealed the child was an ultra rapid metabolizer of codeine. However, there were also other contributing factors; the child had bronchopneumonia and sleep apnea. The study concluded these factors “may have increased his risk of hypoxemia, leading to alterations in opioid receptors and increased sensitivity to morphine.”

 
Canadian Pharmacists Journal concludes these studies show ultra rapid metabolizers of codeine are correlated with a higher risk of morphine intoxication among children.

 

Alternatives to Prevent Adverse Drug Reactions

 
Canadian Pharmacists Journal argues morphine as a safer alternative compared to codeine. They argue morphine has “demonstrated efficacy and relative safety when used appropriately in pain management in both adults and children.” A study they analyzed found morphine treatment more effective than a placebo for children in postoperative pain.

 
Current Opinion in Anesthesiology also outlines the possible alternatives to prevent the risks of opioids, such as pharmacogenetics. They indicate personalized opioid therapy for pain management is “distant from reality”, but current CYP2D6 pharmacogenetic research on codeine is hopeful. The review summarizes, “pharmacogenetics has the potential to guide anesthesia providers on perioperative opioid selection and dosing to maximize efficacy and safety.”

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Pharmacogenetics Emerging as a Method to Guide Medication Therapy

By | Gene Panel, Opioids, Other, Pharmacogenetic Testing, Provider | No Comments

According to a recent article published in American Family Physician “Pharmacogenetics: Using Genetic Data to Guide Drug Therapy (2015), pharmacogenetics is being more widely used by family physicians and the number of patients who are interested in acquiring genetic information is growing.

 

The Components of Pharmacogenetics Testing

 
Pharmacogenetics involves genetic variations that code for drug metabolizing enzymes. It also involves how a medication breaks down in the body and how the body responds to the medication. The most common forms of genetic variations are single nucleotide polymorphisms.

 
The differences in single nucleotide polymorphisms or other polymorphisms result in diverse types of genes or alleles, the American Family Physician explains. Individuals inherit these alleles that “govern expression of the gene and the cor¬responding enzyme or protein.” As a result, these genetic differences influence how the drug reacts in the body and how the body metabolizes the drug.

 

Genetic Variability Can Alter the Effects of Drugs

 
Studies have demonstrated there is a connection between genetic variations and changes in drug levels and effects.

 
CYP2D6 and Opioids

 
The enzyme activity of CYP2D6 is volatile because of single nucleotide polymorphisms and other variations of CYP2D6. American Family Physician indicates codeine metabolism occurs in 90% of patients and results in normal morphine formation. However, 1% to 2% of people are ultra rapid metabolizers of codeine signifying they have an increased risk of morphine toxicity.

 
American Family Physician analyzed a study involving the death of a breastfed infant and a mother who was an ultra rapid metabolizer of codeine. The study demonstrated the infant died of morphine intoxication. There was opioid toxicity in the breast milk, which passed onto the infant.

 
They recommend pharmacogenetic testing for patients who are possible poor or ultra rapid metabolizers of opioids.

 

CYP2C19 and Clopidrogrel

 
Clopidogrel is primarily metabolized in the enzyme CYP2C19. CYP2C19 is highly polymorphic and 80% of individuals metabolize clopidogrel normally. However, 18% to 45% of people have intermediate enzyme activity and 2% to 15% have poor enzyme activity.

 
American Family Physician presents meta-analyses of CYP2C19 poor metabolizers. Poor CYP2C19 metabolizers taking clopidogrel treatment and undergoing percutaneous coronary intervention have a higher risk of cardiovascular death, myocardial infraction, stroke, and stent thrombosis.

 
These results lead to the recommendation that clinicians should consider alternative treatments, such as pharmacogenetic testing of CYP2C19 to guide antiplatelet therapy.

 

The Benefits of Pharmacogenetics

 
American Family Physician examined the clinical implications of pharmacogenetic testing and the various resources available and developing to support the usage of pharmacogenetics in clinical settings. They conclude “pharmacogenetic testing can be a practical tool to optimize drug therapy and avoid medication adverse effects.”

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side effects of opioids

Pharmacogenomic Data May Help Guide Opioid Pharmacotherapy in Patients with Cancer-related Pain

By | Cancer Treatments, Other, Pain Medications, Pharmacogenomics, Provider | No Comments

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.

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Utility of PGx Testing in Hospitals Bolstered by Research on the Pharmacogenetics (PGx) of Antiplatelet Response

By | CMS Cardiac Bundle, Provider | No Comments

MD Labs Has Turnkey PGx Program for Hospital Implementation

Target Audience: Hospital Executives; Hospital-based Cardiologists, Quality Directors and Pharmacists
 
There is mounting evidence on the cost saving opportunities of applying Pharmacogenetic (PGx) testing following percutaneous coronary intervention (PCI) and coronary stent procedures. In concert with an interventional cardiologist, MD Labs has developed a PGx protocol for Catheter Labs that U.S. hospitals are in the process of adopting. This is of particular importance given the new CMS Cardiac Bundle being introduced into hospitals.
 
The benefits of this protocol are bolstered by studies such as the one in Expert Opinion on Drug Metabolism & Toxicology “The pharmacogenetic control of antiplatelet response: candidate genes and CYP2C19” (July 2015) which surveyed clinical outcomes of using pharmacogenetics to guide antiplatelet therapy used for preventing ischemic events in patients with acute coronary syndromes (ACS), percutaneous coronary intervention (PCI) and other indications. The pharmacogenetics of available antiplatelet agents – aspirin, clopidogrel, prasugrel and ticagrelor – were analyzed.
 

CYP2C19 Implicated in Clopidogrel Response Variability

 
The authors found abundant data in its literature meta-analysis supporting the clinical validity of CYP2C19 and clopidogrel response variability among ACS/PCI patients, stating “[t]he increased risks for reduced clopidogrel efficacy among ACS/PCI patients that carry CYP2C19 loss-of-function alleles should be considered when genotype results are available.” It was also found that “insufficient candidate genes” have thus far been implicated for prasugrel or ticagrelor.
 

The Clinical Utility of Pre-emptive PGx Testing for Plavix

 
The authors concluded by citing the need for pre-emptive PGx testing for clopidogrel (Plavix), for which they found a “clear association” with CYP2C19, explaining that pre-emptive pharmacogenetics testing would circumvent the issue of the need for rapid turnaround which is one of the frequently cited barriers to implementing CYP2C19 genetic testing for antiplatelet therapy.
 
A  pre-emptive approach – as offered by genotyping platforms such as MD Labs’ Rxight® – would integrate CYP2C19 genotype data into cath labs and the patient EMRs to alerts prescribers through clinical decision support at the point-of-care if and when clopidogrel is ordered and the patient carries an at-risk CYP2C19 genotype.
 
“Although this model has inherent challenges … pre-emptive CYP2C19 genetic testing has recently been deployed at several academic medical centers,” the authors stated. The authors called for “an ongoing effort towards the application of clinical pharmacogenetics by increasing clinician education and acceptance.”
 

CMS Cardiac Bundle Paves Way for PGx Testing for ACS Patients

 
With the coming of the CMS Cardiac Bundle program for hospitals (effective Oct 1, 2017) there is now added financial incentive to implement PGx testing as part of the standard of care for cardiac patients about to undergo antiplatelet pharmacotherapy.
 
1,200 participating hospitals in 98 metropolitan areas in the U.S. are mandated to be held financially accountable for the costs of heart attacks and bypass surgery under the CMS protocol for cardiac care.  There is therefore significant incentive to reduce costs through various measures such as integrating PGx testing into standing orders for coronary stent procedures and percutaneous coronary interventions (PCIs). For these treatments, anti-platelet pharmacotherapy is an established standard of care to reduce thrombotic risk, with Plavix (clopidogrel) as a first-line agent tested.
 

Implementing PGx in Your Hospital

 
A crucial part of MD Labs’ Rxight® turnkey program is the incorporation of PGx trained and certified pharmacists as part of the protocol to serve as expert resources for physicians and to provide consultations with the patients; pharmacist involvement in patient care has been shown to reduce hospital readmission rates.  DNA test kits are provided by MD Labs, and results are accessible via online provider and patient portals. Contact MD Labs (1-888-888-1932 or info@rxight.com) for details on the PGx protocol as applied to PCI and stent procedures, and how to integrate the Rxight® pharmacogenetics program into your cath lab.

Another Study Confirms Financial Benefit of Pharmacogenetic Testing for Patients Receiving a Stent

By | CMS Cardiac Bundle, Provider | No Comments

Contact MD Labs to Learn How You Can Implement PGx in Your Cath Lab

 
Target Audience: Hospital Executives, Hospital-based Cardiologists, Quality Directors and Pharmacists
 
Evidence continues to grow demonstrating the financial utility and cost-saving opportunity of applying Pharmacogenetic (PGx) testing following coronary stent procedures and percutaneous coronary intervention (PCI). MD Labs, working with an interventional cardiologist, has developed a PGx protocol for Catheter Labs that is being adopted by hospitals around the country. This is especially important given the new CMS Cardiac Bundle being introduced into hospitals.
 
The benefits of this protocol are reinforced by the article “Financial Analysis of CYP2C19 Genotyping in Patients Receiving Dual Antiplatelet Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention” published in the Journal of Managed Care and Specialty Pharmacy (Jul 2015). This study, discussed in the article, analyzed the financial impact of CYP2C19 genotyping for a set of patients with ACS who received percutaneous coronary intervention and coronary stent implantation and were treated with clopidogrel, prasugrel, or ticagrelor in a managed care setting.
 

CYP2C19 Metabolism Determines Clinical Response and Adverse Events in Plavix Users

 
Diminished CYP2C19 activity impairs clopidogrel metabolism and thereby increases risk of adverse clinical outcomes. Specifically, slow and intermediate CYP2C19 metabolizers treated with clopidogrel suffer higher cardiovascular event rates – including myocardial infarction, stent thrombosis, and stroke – than patients with normal CYP2C19 genotypes, and conversely rapid metabolizers are found to be hypo-responsive. It was concluded from the study that clopidogrel should be used as a first-line agent for all but this subset of patients.
 

Pharmacogenetics Reduces Costs by an Estimated $444K Annually, per One Thousand Patients

 
A budget impact analysis based on market share rates was conducted using overall and average cost per patient modelling based on the rate of CYP2C19 genotyping in a theoretical patient cohort. The magnitude of the financial impact from CYP2C19 genotype-guided antiplatelet therapy was emphasized, and it was expected that use of CYP2C19 genotyping would displace market share from clopidogrel to either prasugrel or ticagrelor. Total estimated annual costs of adverse clinical outcomes (e.g., MI, bleeding, stroke) and antiplatelet treatment were measured. The analysis showed an estimated annual savings of roughly $444,852 when PGx was employed in all patients in the theoretical 1,000 person cohort versus none.
 
Contact MD Labs to learn more. 1-888-888-1932 or info@Rxight.com

More Time To Prepare for the CMS Cardiac Bundle Program – Start Date Pushed to Oct 1 2017

By | CMS Cardiac Bundle, Provider | No Comments

Contact MD Labs to Learn How You Can Implement PGx in Your Cath Lab

 
Target Audience: Hospital Executives, Hospital-based Cardiologists, Quality Directors and Pharmacists
 
The CMS (Centers for Medicare & Medicaid Services) has pushed the implementation of its bundled payment initiatives for cardiac care from July 1 to Oct. 1, 2017, according to an interim final rule posted to the Federal Register “Medicare Program; Advancing Care Coordination Through Episode Payment Models (EPMs); Cardiac Rehabilitation Incentive Payment Model; and Changes to the Comprehensive Care for Joint Replacement Model; Delay of Effective Date.”
 

New Start Date Gives Hospitals Additional Preparation Time

 
The three-month delay “allow[s] time for additional review, to ensure that the agency has adequate time to undertake notice and comment rulemaking to modify the policy if modifications are warranted, and to ensure that in such a case participants have a clear understanding of the governing rules and are not required to take needless compliance steps,” the interim rule stated.
 

The Utility of PGx Testing for Hospital Cost Reduction

 
Under the CMS bundled payment initiative, participating hospitals in 98 metropolitan areas in the U.S. are mandated to be held financially accountable for the costs of heart attacks and bypass surgery, and thus have incentive to reduce costs through various measures such as integrating PGx testing into standing orders for coronary stent procedures and percutaneous coronary interventions (PCIs). For these treatments, anti-platelet pharmacotherapy is an established standard of care to reduce thrombotic risk, with Plavix (clopidogrel) as a first-line agent tested.
 
Pharmacogenetic testing is shown to reduce drug-related complications and readmission rates, thus sparing added costs to hospitals and providers, as discussed in a recent report out of the University of Illinois Hospital & Health Sciences System, which demonstrated that pharmacogenetic testing reduced 90-Day ER and Hospital Readmission Rates by 68 percent.
 

Contact MD Labs for Information on the CMS Initiative and its Turnkey PGx Testing Program

 
Contact MD Labs (1-888-888-1932) or info@Rxight.com) for details on the PGx protocol as applied to PCI and stent procedures, and how to integrate its Rxight® PGx program into your hospital lab.
 
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 also proven to help reduce readmission rates. The Rxight® Program provides turnkey implementation and includes pharmacist training in PGx and certification to conduct PGx consultations. DNA test kits are provided by MD Labs, and results are accessible via online provider and patient portals.

Pharmacogenetics of Methylphenidate (Ritalin) in ADHD

By | Provider | No Comments

Methylphenidate (MPH), branded as Ritalin, Concerta, Daytrana, Methylin, and Aptensio, is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). There is, however, considerable interindividual variability exists in clinical outcomes, which may arise from underlying genetic influences coupled with environmental influences, as discussed in a January 2017 article in The Pharmacogenomics Journal “Pharmacogenetics of methylphenidate response and tolerability in ADHD.”
 
The study is the first of its kind examining multiple SNPs across genes encoding the main components of the dopaminergic system to identify genetic factors that moderate response variability in ADHD treatment, according to the authors.
 
Specifically, the study was based in the analysis of 57 single-nucleotide polymorphisms (SNPs) in nine dopamine-related candidate genes (TH, DBH, COMT, DAT1 and DRD1-5) as potential predictors of methylphenidate efficacy and tolerability, and additionally considered teratogenic and postnatal xenotoxins (specifically maternal nicotine use)  as factors.
 
In analyzing the clinical efficacy of MPH, researchers found a “[a]dverse events after MPH treatment were significantly associated with variation in DBH  and DRD2. This study suggests that the geneticallly modulated dopaminergic system together with xenobiological and teratogenic influences may moderate MPH treatment effects.
 
“[C]linical response to MPH may be the result of a much more complex matrix of factors, including both genetic and environmental risks,” the authors concluded, calling for [f]urther pharmacogenetic studies with larger samples are required to fully validate these results and to disentangle the impact of prenatal xenotoxins on clinical response to MPH in genetically susceptible individuals.”

African Genetic Diversity: Implications for Cytochrome P450-mediated Drug Metabolism

By | Provider | No Comments

Continental African populations are characterized by high levels of genetic diversity in a high proportion of patients who experience adverse reactions to a range of pharmacotherapeutic approaches when compared to Caucasian and Asian populations, which the majority of research on pharmacogenetics have hitherto considered for analysis.
 
A February 2017 article  in EBioMedicine “African Genetic Diversity: Implications for Cytochrome P450-mediated Drug Metabolism and Drug Development” (Rajman, I., et al.) addressed the necessity for such research, presenting findings on the identification of CYP alleles of potential clinical relevance in the African population based in literature review.
 
Specifically, the study employed a statistical method known as PCA (principle component analysis) grounded in text mining publications to find references to global populations including Africa for the purpose of comparative analysis. Sixteen CYP variants were considered.
 
The authors, who confirmed that there is in fact greater diversity in CYP distribution in Africa than in other continental populations, identified a necessity for optimization of drug therapy and drug development for Africa, which currently “carries a high burden of adverse drug reactions owing to the use of old, poorly optimized drugs.”
 
Pharmacogenetic findings on African-Americans are often erroneously extrapolated to the African population, the article states, noting that it is not representative of the variety of populations present in the African continent.  “The African continent cannot … be treated as a single entity in drug research and development, nor can African-American populations be considered an adequate proxy for pharmacogenetic differences across Africa,” the authors stated,
 
The researchers called for a need to study in depth CYP variants in Africans and, moreover, to raise awareness of the greater genetic variation among this population when applied to drug metabolism and efficacy,  stating “[t]he involvement of clinicians in genomic research will facilitate this translation process, helping to ensure that patients are treated with efficacious doses of therapeutic drugs.”

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.”

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