|
| A) | The College of American Pathologists | ||
| B) | The American Pharmacists Association | ||
| C) | The Department for Health and Human Services | ||
| D) | The U.S. Food and Drug Administration's Center for Drug Evaluation and Research |
The role of genetic factors in an individual's response to drug therapy has become an area of increasing interest in medicine and pharmacy[1]. 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 [2]. 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 [2,3]. 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 [2]. 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 [4].
| A) | not a well-defined discipline of pharmacology. | ||
| B) | not easily applied to the practice of medicine and nursing. | ||
| C) | how an individual's genetic makeup is altered by pharmacotherapy. | ||
| D) | the study of how an individual's genetic makeup affects his or her response to drugs. |
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 [5]. 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 [5].
| A) | 0.2% to 1% | ||
| B) | 2% to 9% | ||
| C) | 20% to 95% | ||
| D) | 100% |
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 [5]. 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 [6]. This serves as the basis for pharmacogenetic testing as a method of determining which drugs can provide optimal treatment for any given patient [6].
| A) | FVL | ||
| B) | CYP2C9 | ||
| C) | UGT1A1 | ||
| D) | HLA-B44 |
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 at increased risk for serious adverse effects with the administration of the chemotherapy drug irinotecan, including diarrhea and hematopoietic toxicity [2,4,10].
| A) | Acquired and inherited | ||
| B) | Short- and long-term findings | ||
| C) | Ancillary and essential findings | ||
| D) | The type of genetic variation identified by the test and the goal of the testing process |
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) [17]. A classification framework has been developed to guide testing and treatment decisions related to pharmacogenetic testing (Figure 1) [17].
| A) | determining family health risks. | ||
| B) | improvement of hypothetical future care. | ||
| C) | possible tumor and/or other disease tissue growth prior to the selection of drug therapy. | ||
| D) | All of the above |
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 [17]. 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 various tyrosine kinase inhibitors (e.g., afatinib, erlotinib, gefitinib, lapatinib, osimertinib, rociletinib, sunitinib, dasatinib) [18,19]. 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 [19]. 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 [20]. 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 [21,22]. 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.
| A) | BRCA1 | ||
| B) | CYP2C9*1/*1 | ||
| C) | VKORC1-1639AA | ||
| D) | Epidermal growth factor gene |
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 [17]. 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 various tyrosine kinase inhibitors (e.g., afatinib, erlotinib, gefitinib, lapatinib, osimertinib, rociletinib, sunitinib, dasatinib) [18,19]. 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 [19]. 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 [20]. 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 [21,22]. 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.
| A) | Cancer | ||
| B) | Diabetes | ||
| C) | Attention deficit hyperactivity disorder | ||
| D) | Both A and C |
SELECTED CLINICAL PHARMACOGENETIC TESTING AND APPLICATION
| Disease/Condition | Drug/Agent | Genotype Test | Therapeutic Consideration |
|---|---|---|---|
| Anticoagulation therapy | Warfarin | CYP2C9 and VKORC1 | Optimal dose |
| Anti-platelet therapy for acute coronary syndrome | Clopidogrel | CYP2C19 | Switch to prasugrel or other alternative therapy |
| Tuberculosis | Isoniazid | NAT2 | Establish minimum effective dose |
| Metastatic colon cancer and other solid tumor cancers | High-dose irinotecan | UGT1A1 | Optimal initial dose |
| Immune diseases | Thiopurine family drugs (azathioprine, mercaptopurine, and thioguanine) | TPMT | Optimal initial dose |
| Non-small-cell lung cancer | Tyrosine kinase inhibitors | EGFR | Treatment selection |
| Breast cancer | Anti-HER2 therapies (e.g., lapatinib, pertuzumab, trastuzumab, trastuzumab emtansine) | HER2 | Treatment selection (i.e., decide use of HER2-targeted therapies) |
| Hormone-dependent breast cancer | Tamoxifen | CYP2D6 | Optimal dose |
| Metastatic colorectal cancer | Anti-EGFR-targeted drugs (e.g., cetuximab, panitumumab) | KRAS | Predict therapeutic effect |
| Attention deficit hyperactivity disorder | Atomoxetine | CYP2D6 | Optimal dose |
| Analgesia | Codeine | CYP2D6 | Optimal dose |
| Depression (and other uses) | Tricyclic antidepressants | CYP2D6 | Optimal dose |
| A) | Misattributed paternity | ||
| B) | Discovering disturbing information | ||
| C) | Findings that cannot be addressed medically | ||
| D) | Missing an opportunity to address an actionable issue |
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 [25]. 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) [26]. 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 [25,27]. 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.
| A) | Allocation of scarce resources | ||
| B) | Decision-making for impaired patients | ||
| C) | Genetic testing in newborns, infants, and children | ||
| D) | Protecting the confidentiality of stored genetic information |
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 [28]. 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) [28].
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 [29]. If there is clinical relevance and 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) [25,29].
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. Researchers reviewed 111 laboratories that offer clinical pharmacogenetic testing in the United States. Of these, 76 offered pharmacogenetic testing services, including 31 that offered tests only for specific genes, 30 that offered tests for multiple genes, and 15 that offered both types of tests. A total of 45 laboratories offered 114 multigene panel tests that cover 295 genes; however, no clinical guidelines were available for most of the tests [30]. Despite the lack of consensus on preventive pharmacogenetic testing, many healthcare organizations have implemented testing programs to obtain information regarding clinical validity and usefulness [31,32,33,34].