Pharmacogenetics is the study of the impact that inheritance and genetic variability can have on drug response and ultimately the selection of a specific drug for a particular individual. The use of pharmacogenetic testing is becoming an increasing well recognized process in the medical and scientific communities. The ability to determine the types of responses may be elicited by a particular drug serves as a monumental breakthrough in terms of optimizing drug therapy and improving healthcare outcomes. Because it has become possible to identify specific genes and their connection to drug response in certain individuals, this has both garnered both supporters and opponents who view significant ethical impactions with the growing adoption of this new healthcare advancement.
This course is designed for physicians, nurses, physician assistants, and pharmacists who assess and make decisions regarding the appropriate pharmacotherapy for their patients.
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The purpose of this course is to educate healthcare professionals about pharmacogenetics and its application in drug selection and therapeutic interventions.
Upon completion of this course, you should be able to:
- Describe the background of pharmacogenetic testing.
- Discuss the types of pharmacogenetic testing and their applications.
- Examine the ethical implications of pharmacogenetic testing.
Abimbola Farinde, MS, PharmD, is a clinical pharmacy specialist who has gained experience in the field and practice of psychopharmacology/mental health and geriatric pharmacy. She has worked with active-duty soldiers with dual diagnoses of a traumatic brain injury and a psychiatric disorder, providing medication therapy management and disease state management. Dr. Farinde has also worked with mentally impaired and developmentally disabled individuals at a state-supported living center. Her different practice experiences have allowed her to develop and enhance her clinical and medical writing skills over the years. Dr. Farinde always strives to maintain a commitment toward achieving professional growth as she transitions from one phase of her career to the next.
Contributing faculty, Abimbola Farinde, MS, PharmD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
John M. Leonard, MD
Jane C. Norman, RN, MSN, CNE, PhD
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
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#95100: An Introduction to Pharmacogenetic Testing
The role of genetic factors in an individual's response to drug therapy has become an area of increasing interest in medicine and pharmacy . Over the years, significant progress has been made toward the application of pharmacogenetic testing when it comes to the selection of drug therapies for a variety of patient populations . The U.S. Food and Drug Administration's (FDA's) Center for Drug Evaluation and Research (CDER) has begun to require some manufacturers to provide pharmacogenetic-specific information on product labels to alert prescribers that pharmacogenetic testing may be required prior to the first dose of a drug or drug class . A proficiency testing program for pharmacogenetics was introduced by the College of American Pathologists (CAP), in part with the goal of identifying drugs that should be relabeled by the FDA CDER. Since the inception of the program, five genes with significant impact on the response to drug testing have been recognized . These initial steps have been instrumental in fostering a growing awareness of the application of pharmacogenetic testing, which, while limited, has the opportunity to grow with ongoing and future research .
Pharmacogenetics is the study of how an individual's genetic makeup affects his or her response to drugs. It is a well-defined discipline of pharmacology, with principles that can be applied to the practice of medicine and nursing . All genes in the body can be analyzed, and each drug interacts with numerous proteins in each gene. The presence of genetic variations in a large number of genes can affect the response to the drug. Eventually, the use of pharmacogenetics may lead to genotype-based individualized therapy instead of the traditional approach of one-size-fits-all pharmacotherapy .
The basis of pharmacogenetics is the belief that drug response can be fueled by pharmacokinetic and pharmacodynamic changes spurred by an individual's genotype. The discovery of a new disease susceptibility gene can lead to more individualized prescriptions and an increased likelihood that an individual is able to receive the most effective drug and dose during initial therapy . It is estimated that genetic factors can be attributed to 20% to 95% of the variations that occur in individual responses to medications, and the identification of these gene variants has the potential to impact an individual's ultimate outcome . This serves as the basis for pharmacogenetic testing as a method of determining which drugs can provide optimal treatment for any given patient .
During the years since the development of the proficiency testing program for pharmacogenetics, several gene variants with significant impact on response to drug therapy have been identified, including [6,7,8]:
Variants in the gene for uridine diphosphate (UDP) glucuronosyltransferase 1A1 (UGT1A1)
Patients with variant alleles for cytochrome P450, or CYP2C9 (*2, *3)
Vitamin K epoxide reductase complex subunit
There are specific instances in which the identification and testing of these genes can prove to be important to clinical decision making. For example, testing for variations in UGT1A1 can be vital in the identification of individuals who are an increased for hematopoietic toxicity with the administration of the chemotherapy drug irinotecan [2,9].
The clinical implementation of pharmacokinetic testing will be highly dependent on the applicability, usability, and accuracy of genotyping. There were initially few clinical guidelines that linked the result of pharmacogenetic tests to specific therapeutic recommendations, but systematic literature reviews have led to recommendations for 53 different drugs that are associated with the gene coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), UGT1A1, HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL) [10,11]. Variability in the coding by these genes can help guide the selection and development of more effective therapeutic interventions with less potential for serious adverse effects.
With the increasing number of pharmacogenetic tests becoming available, the requirement by the FDA for drug labels to possess pharmacogenetic information may become a standard of practice over time [11,12]. There is a divergence in the stance that regulatory authorities and clinicians take when it comes to pharmacogenetic testing. On one hand, there is an increased expectation for more personalized medicine development. On the other hand, some experts recommend exercising caution, with a focus more on pharmacogenetic testing's ability to improve the likelihood of achieving benefit effects and lowering specific toxic effects rather than its potential to direct drug development .
The ability to apply the concepts of pharmacogenetic testing to clinical practice is one of the most promising aspects of genomic research. The two key components in clinical settings are the type of genetic variation identified by the test (i.e., inherited or acquired) and the goal of the testing process (i.e., to address a specific issue or to gather information for future care) . A classification framework has been developed to guide testing and treatment decisions related to pharmacogenetic testing (Figure 1) .
This classification consists primarily of tests for either acquired or inherited variants. Acquired genetic variants are involved in testing for possible tumor and/or other disease tissue growth prior to the selection of the most beneficial drug therapy . For instance, tests for mutation in the epidermal growth factor gene may be done for patients with non-small cell lung cancer to determine which patients are more likely to respond to the tyrosine kinase inhibitors erlotinib, gefitinib, lapatinib, sunitinib, or dasatinib [17,18]. Testing for inherited genetic variations is intended to improve the future level of care. Patients will ultimately require drug treatment, which may be guided by information gleaned from the test results. As the use of prescription drugs continues to increase in the United States, the requirement for pharmacogenetic testing may as well. For example, there has been an increase in the use of warfarin algorithms to estimate the therapeutic dose for those with either existing genetic or nongenetic factors . The algorithm uses linear regression models (y=ax+b) in order to arrive at the therapeutic warfarin dose, with factors identified as independent variables (i.e., the x variables) included in the model . Take for example a white woman who is 70 years of age, is 5 feet 5 inches tall, weighs 70 kilograms, and carries VKORC1-1639AA and CYP2C9*1/*1 genotypes. She is a nonsmoker and is being treated for atrial fibrillation with a target INR of 2.5. Based on the model estimates, the warfarin dose is set at 3.74 mg/day. The algorithm provides an estimated warfarin dose, while a pharmacogenetic dosing table can assist with the selection of the first dose of warfarin if a patient has a CYP2CP and VKORC1 genotype [20,21]. This practice of pharmacogenetic testing is not required for the initiation of warfarin dosing; it is at the discretion of the clinician to order the test. Further research is necessary to determine the effectiveness of genotype-guided care over adherence to established clinical algorithms and guidelines.
Besides testing for acquired or inherited genetic variation to assist with the improvement of current care, there is also combined testing for inherited/acquired variants. In special circumstances, an individual may exhibit with both an acquired and an inherited variant affecting drug selection. For example, a drug belonging to the class of a tyrosine kinase inhibitor may be metabolized by a highly variable CYP3A4 enzyme. Therefore, in addition to testing for particular genetic predisposition, testing should also be performed to assess the level of CYP3A4 activity [20,21]. Whereas CYP3A4 activity may be affected by an inherited variant, an acquired variant may also impact how the patient reacts to the selected drug.
It is important that testing for acquired variants, inherited variants, or a combination of acquired/inherited variants is performed in a timely manner to help to guide and make treatment decisions. For example, if an elderly patient has been diagnosed with rectal cancer, the rapid testing process to produce a pharmacogenetic profile may lead to the immediate initiation of effective cancer treatment. The pharmacogenetic profile may guide the selection of a chemotherapeutic treatment plan that is more appropriate for this patient given that host genetic variability has been shown to be a vital component in the individualization of cancer treatment [22,23].
Although pharmacogenetic testing can be a valuable tool to predict an individual's response to the administration of a drug, there are ethical issues regarding the growing use of this testing process. Genome sequencing has the potential to remove the need for individual genetic formation tests, but there are concerns that sequencing may reveal information that some would prefer to not know (e.g., misattributed paternity, findings that cannot be addressed medically) . It is important that all patients provide informed consent prior to any genetic testing. In addition to the right to know, patients also have the right not to know. There are risks associated with knowing (e.g., discovering disturbing information) and with not knowing (e.g., missing an opportunity to address an actionable issue), and these points should be explained and understood by each patient . For patients for whom English is not their first language, forms should be presented in the language they feel most comfortable with. The use of a trained interpreter is also recommended in order to minimize any potential misunderstandings and liabilities.
Another ethical issue is whether the use of pharmacogenetic testing constitutes a reasonable allocation of scarce resources and whether it will widen the disparities in access to health care. In order to support the clinical utility of widespread pharmacogenetic testing, cost savings, such as the avoidance of adverse reactions and hospitalizations through the identification of genetic variants, should be demonstrated . Due to the additional cost and potential reimbursement issues, pharmacogenetic testing may end up being unequally available to those with the means to pay for the services. In addition, drug companies may cease developing drugs to treat conditions that affect a small number of patients (as identified through genetic markers) .
There has also been debate as to whether pharmacogenetic testing should be performed on newborns, infants, and children. While newborn screening has become commonplace, genetic tests in children have not. The rationale for genetic testing should be clearly defined so patients and guardians are able to make informed consent . If there is a therapeutic intent behind the use of pharmacogenetic testing in infants and children, the test may be used, but a discussion should occur about the broader implications (e.g., how to proceed with secondary or ancillary findings) .
The confidentiality of stored genetic information is also a concern. There is a risk that insurance providers and/or employers may gain access to test results, violating patient confidentiality. However, the United States is in the process of developing laws to prevent discrimination based on genetic makeup .
Although ethical and scientific concerns remain regarding this relatively new genetic technology, pharmacogenetic testing is undergoing substantial growth and may allow researchers and clinicians to engage in gene profiling in order to better predict patients' response to pharmacotherapy. This could ultimately result in the development of safer and more effective drug therapies and/or treatment protocols. The application of pharmacogenetic testing is becoming a reality for a variety of clinical conditions, and the subsequent drug developments may foster the widespread adoption of pharmacogenetic testing as a valid diagnostic and prescriptive tool in health care . Some areas of pharmacogenetic testing have yet to be fully examined. However, to date it has helped to shape clinical guidelines and has the potential to provide greater insight for healthcare providers when it comes to effectively treating patients.
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