File Name: pharmacogenomics an introduction and clinical perspective .zip
- Pharmacogenomics and regulatory decision making: an international perspective
- Pharmacogenomics: Overview, Applications, and Recent Developments
Pharmacogenomics PGx is the science of understanding the interaction between genes and drugs. The analysis of specific areas of the DNA provides information about a certain drug metabolism and about the expected response to a certain treatment. PGx also aims to reduce the incidence of adverse drug events ADEs. The causes of individual responses to a same drug dosage include age, genetic and immunological factors, comorbidities and interaction between active principles.
Pharmacogenomics and regulatory decision making: an international perspective
Pharmacogenomics is the study of the role of the genome in drug response. Although both terms relate to drug response based on genetic influences, pharmacogenetics focuses on single drug- gene interactions, while pharmacogenomics encompasses a more genome-wide association approach, incorporating genomics and epigenetics while dealing with the effects of multiple genes on drug response.
Pharmacogenomics aims to develop rational means to optimize drug therapy , with respect to the patients' genotype , to ensure maximum efficiency with minimal adverse effects.
Pharmacogenomics also attempts to eliminate the trial-and-error method of prescribing, allowing physicians to take into consideration their patient's genes, the functionality of these genes, and how this may affect the efficacy of the patient's current or future treatments and where applicable, provide an explanation for the failure of past treatments.
For patients who have lack of therapeutic response to a treatment, alternative therapies can be prescribed that would best suit their requirements. In order to provide pharmacogenomic recommendations for a given drug, two possible types of input can be used: genotyping or exome or whole genome sequencing.
Pharmacogenomics was first recognized by Pythagoras around BC when he made a connection between the dangers of fava bean ingestion with hemolytic anemia and oxidative stress. This identification was later validated and attributed to deficiency of G6PD in the s and called favism. There are several known genes which are largely responsible for variances in drug metabolism and response.
The focus of this article will remain on the genes that are more widely accepted and utilized clinically for brevity.
These enzymes introduce reactive or polar groups into xenobiotics such as drugs. CYP proteins are conveniently arranged into these families and subfamilies on the basis of similarities identified between the amino acid sequences. CYP2B6 plays an important role in the metabolism of drugs including the anti-HIV drug efavirenz , the anti-malarial artemisinin , the antidepressants bupropion and ketamine , the anticancer drug cyclophosphamide , and the opioid methadone.
The higher prevalence of central nervous system side effects in African as compared to American and European patients treated with efavirenz has been attributed to the higher frequency of the CYP2B6 slow metabolizer phenotype in sub-Saharan African populations. Also known as debrisoquine hydroxylase named after the drug that led to its discovery , CYP2D6 is the most well-known and extensively studied CYP gene. More than CYP2D6 genetic variants have been identified. For certain drugs predominantly metabolized by CYP2D6, these variations can lead to unusually high or low drug concentrations in serum Referred to as poor metabolizer and ultra metabolizer phenotypes, respectively , thus leading to increased side effects or reduced efficacy.
Commonly affected drugs include tramadol, venlafaxine, morphine, mirtazapine, and metoprolol. Discovered in the early s, CYP2C19 is the second most extensively studied and well understood gene in pharmacogenomics.
Individuals with polymorphism in this have an affected response to warfarin treatment. Thiopurine methyltransferase TPMT catalyzes the S-methylation of thiopurines, thereby regulating the balance between cytotoxic thioguanine nucleotide and inactive metabolites in hematopoietic cells.
Excessive levels of 6-MP can cause myelosuppression and myelotoxicity. Prometheus Laboratories, Inc. Codeine , clopidogrel , tamoxifen , and warfarin a few examples of medications that follow the above metabolic pathways. The two extremes of this spectrum are the poor metabolizers and ultra-rapid metabolizers. Efficacy of a medication is not only based on the above metabolic statuses, but also the type of drug consumed.
Drugs can be classified into two main groups: active drugs and prodrugs. Active drugs refer to drugs that are inactivated during metabolism, and prodrugs are inactive until they are metabolized. For example, we have two patients who are taking codeine for pain relief.
Codeine is a prodrug, so it requires conversion from its inactive form to its active form. The active form of codeine is morphine, which provides the therapeutic effect of pain relief. Although both individuals are taking the same dose of codeine, person B could potentially lack the therapeutic benefits of codeine due to the decreased conversion rate of codeine to its active counterpart morphine.
Each phenotype is based upon the allelic variation within the individual genotype. However, several genetic events can influence a same phenotypic trait, and establishing genotype-to-phenotype relationships can thus be far from consensual with many enzymatic patterns. The list below provides a few more commonly known applications of pharmacogenomics: . Pharmacogenomics may be applied to several areas of medicine, including pain management , cardiology , oncology , and psychiatry.
A place may also exist in forensic pathology , in which pharmacogenomics can be used to determine the cause of death in drug-related deaths where no findings emerge using autopsy. In cancer treatment , pharmacogenomics tests are used to identify which patients are most likely to respond to certain cancer drugs.
In behavioral health, pharmacogenomic tests provide tools for physicians and care givers to better manage medication selection and side effect amelioration. Pharmacogenomics is also known as companion diagnostics, meaning tests being bundled with drugs.
Beside efficacy, germline pharmacogenetics can help to identify patients likely to undergo severe toxicities when given cytotoxics showing impaired detoxification in relation with genetic polymorphism, such as canonical 5-FU.
In cardiovascular disorders , the main concern is response to drugs including warfarin , clopidogrel , beta blockers , and statins. In , the largest private health insurer, UnitedHealthcare, announced that it would pay for genetic testing to predict response to psychiatric drugs; as of , it is the only private insurer to offer such coverage. In , Canada's 4th largest health and dental insurer, Green Shield Canada, announced that it would pay for pharmacogenetic testing and its associated clinical decision support software to optimize and personalize mental health prescriptions.
Case A — Antipsychotic adverse reaction . Patient A suffers from schizophrenia. Their treatment included a combination of ziprasidone, olanzapine, trazodone and benztropine. The patient experienced dizziness and sedation, so they were tapered off ziprasidone and olanzapine, and transitioned to quetiapine.
Trazodone was discontinued. The patient then experienced excessive sweating, tachycardia and neck pain, gained considerable weight and had hallucinations. Five months later, quetiapine was tapered and discontinued, with ziprasidone re-introduction into their treatment due to the excessive weight gain.
Although the patient lost the excessive weight they gained, they then developed muscle stiffness, cogwheeling , tremors and night sweats. When benztropine was added they experienced blurry vision. After an additional five months, the patient was switched from ziprasidone to aripiprazole. Over the course of 8 months, patient A gradually experienced more weight gain, sedation, developed difficulty with their gait, stiffness, cogwheeling and dyskinetic ocular movements.
Case B — Pain Management . Patient B is a woman who gave birth by caesarian section. Her physician prescribed codeine for post-caesarian pain.
She took the standard prescribed dose, however experienced nausea and dizziness while she was taking codeine. She also noticed that her breastfed infant was lethargic and feeding poorly. When the patient mentioned these symptoms to her physician, they recommended that she discontinue codeine use.
Within a few days, both the patient and her infant's symptoms were no longer present. It is assumed that if the patient underwent a pharmacogenomic test, it would have revealed she may have had a duplication of the gene CYP2D6 placing her in the Ultra-rapid metabolizer UM category, explaining her ADRs to codeine use. Codeine is converted to morphine by CYP2D6, and those who have UM phenotypes are at danger of producing large amounts of morphine due to the increased function of the gene.
The morphine can elevate to life-threatening or fatal amounts, as became evident with the death of three children in August A potential role pharmacogenomics may play would be to reduce the occurrence of polypharmacy. It is theorized that with tailored drug treatments, patients will not have the need to take several medications that are intended to treat the same condition.
In doing so, they could potentially minimize the occurrence of ADRs, have improved treatment outcomes, and can save costs by avoiding purchasing extraneous medications. An example of this can be found in psychiatry , where patients tend to be receiving more medications than even age-matched non-psychiatric patients. This has been associated with an increased risk of inappropriate prescribing. The need for pharmacogenomics tailored drug therapies may be most evident in a survey conducted by the Slone Epidemiology Center at Boston University from February to April The U.
Food and Drug Administration FDA appears to be very invested in the science of pharmacogenomics  as is demonstrated through the and more FDA-approved drugs that include pharmacogenomic biomarkers in their labels. The guide is intended to address the use of genomic information during drug development and regulatory review processes.
Although there appears to be a general acceptance of the basic tenet of pharmacogenomics amongst physicians and healthcare professionals,  several challenges exist that slow the uptake, implementation, and standardization of pharmacogenomics. Some of the concerns raised by physicians include:   . Issues surrounding the availability of the test include: . Although other factors contribute to the slow progression of pharmacogenomics such as developing guidelines for clinical use , the above factors appear to be the most prevalent.
Increasingly substantial evidence and industry body guidelines for clinical use of pharmacogenetics have made it a population wide approach to precision medicine. Cost, reimbursement, education, and easy use at the point of care remain significant barriers to widescale adoption. Some alleles that vary in frequency between specific populations have been shown to be associated with differential responses to specific drugs.
The beta blocker atenolol is an anti- hypertensive medication that is shown to more significantly lower the blood pressure of Caucasian patients than African American patients in the United States. Computational advances have enabled cheaper and faster sequencing. As the cost per genetic test decreases, the development of personalized drug therapies will increase.
This a huge step towards bringing pharmacogenetic technology into everyday medical decisions. The companies use the same genotyping chips that are used in GWAS studies and provide customers with a write-up of individual risk for various traits and diseases and testing for , known SNPs.
The more expensive packages even included a telephone session with a genetics counselor to discuss the results. Pharmacogenetics has become a controversial issue in the area of bioethics. Privacy and confidentiality are major concerns. From Wikipedia, the free encyclopedia. Branch of science. For the journal, see Pharmacogenomics journal. Genome Heredity Mutation.
Nucleotide Variation. Outline Index. Introduction History. Further information: Education in personalized medicine. Biology portal Technology portal Medicine portal. Emerging Medical Technologies.
Handbook of Pharmacogenomics and Stratified Medicine is a comprehensive resource to understand this rapidly advancing field aiming to deliver the right drug at the right dose to the right patient at the right time. It is designed to provide a detailed, but accessible review of the entire field from basic principles to applications in various diseases. The chapters are written by international experts to allow readers from a wide variety of backgrounds, clinical and non-clinical basic geneticists, pharmacologists, clinicians, trialists, industry personnel, ethicists to understand the principles underpinning the progress in this area, the successes, failures and the challenges ahead. It is well known that people respond differently to medications and in many cases the risk-benefit ratio for a particular drug may be a gray area. The last decade has seen a revolution in genomics both in terms of technological innovation and discovering genetic markers associated with disease. In parallel there has been steady progress in trying to make medicines safer and tailored to the individual. This has occurred across the whole spectrum of medicine, some more than others.
Pharmacogenomics: Overview, Applications, and Recent Developments
Pharmacogenomics is defined as the study of genes and how an individual response is affected due to drugs. Pharmacogenomics is an emerging new branch with combination of both pharmacology the branch of science that deals with study of drugs as well as genomics the branch of science that deals with study of genes for development of effective doses and safe medications tailored according an individual patient genetic makeup. Difference in genetic makeup provides difference in effectiveness of medication and in future to predict effectiveness of medication for an individual and to study existence of adverse drug reactions. Besides advancement in the field of science and technology till date pharmacogenomics hangs in infancy. There is limited use of pharmacogenomics, but still, novel approaches are under clinical trials.
Shaun Walsh, B. This overview of the current state of pharmacy informatics discusses the applications and limitations of all aspects of this field, as well as opportunities for the future. The purpose is to provide an introduction to pharmacy informatics and to the role of informatics in the practice of pharmacy.
Understanding an individual's genetic makeup is the key to creating personalized drugs with greater efficacy and safety, and pharmacogenomics aims to study the complex genetic basis of inter-patient variability in response to drug therapy. Based upon the success of its first edition, the second edition of Pharmacogenomics: Methods And Protocols aims to continue providing readers with high-quality content on the most innovative and commonly adopted technologies in the field of pharmacogenomics as presented by experts in the field. Broken into several sections, this detailed volume examines techniques for interrogating variation in human genes and genomes, functional assessment of genetic variation, both in vitro and in vivo, as well as tools for translation and implementation of pharmacogenetic markers. Skip to main content Skip to table of contents. Advertisement Hide.
The only pharmacogenomics resource to feature a global author team comprised of PharmDs, MDs, PhDs and social scientists, Pharmacogenomics offers an essential, highly accessible survey of this dynamic discipline. You will find thorough coverage of all need-to-know topics, from individual molecules to systemic diseases, plus an examination of the latest technologies that are constantly reshaping the field. Pharmacogenomics is cohesively organized into two sections, the first of which reviews basic aspects of pharmacogenomics, including ethics, regulatory, science, and drug metabolism, along with a "mini" course in molecular genetics and testing. The second section highlights the practical application of pharmacogenomics in cardiovascular medicine, immunology, neurology, and other specialties.
This succinct handbook provides students and practitioners with clinically relevant psychotropic drug information. The Eighth Edition is designed as a reference text that also teaches by delivering informative narrative text under standard headlin