Pediatric Annals

Special Issue Article 

Pharmacogenomic Primer for the Pediatrician—What Is Really Important?

Shannon Manzi, PharmD, BCPPS

Abstract

Safe prescribing of medications has become increasingly challenging with dozens of new drugs and drug classes added each year. Maximizing the ability to find a medication that will work as intended while minimizing side effects can be difficult, particularly when a patient does not respond as expected. Some of the variability in response may be attributed to the patient's genetics. Pharmacogenomics is the science of examining a patient's genotype in the context of medication selection and dosing. Used correctly, the clinical application of pharmacogenomic data can be useful in decreasing the trial and error approach to medication therapy. [Pediatr Ann. 2018;47(5):e217–e219.]

Abstract

Safe prescribing of medications has become increasingly challenging with dozens of new drugs and drug classes added each year. Maximizing the ability to find a medication that will work as intended while minimizing side effects can be difficult, particularly when a patient does not respond as expected. Some of the variability in response may be attributed to the patient's genetics. Pharmacogenomics is the science of examining a patient's genotype in the context of medication selection and dosing. Used correctly, the clinical application of pharmacogenomic data can be useful in decreasing the trial and error approach to medication therapy. [Pediatr Ann. 2018;47(5):e217–e219.]

Pharmacogenomics is the study and application of gene expression influence on the metabolism of drugs, affecting both pharmacokinetics and pharmacodynamics. Along with the promise of what pharmacogenomics can tell us comes the reality of what it cannot. There is no magic test, no crystal ball, despite what you may hear otherwise from companies that market pharmacogenomic assays. Human drug metabolic pathways are for the most part exceedingly complex, influenced by a variety of factors including but not limited to genetics. Currently, the primary focus of commercial pharmacogenomics testing is the CYP450 enzymes and a few other pathways such as thiopurine methyltransferase that have actionable consequences. Research panels, whole exome, and whole-genome testing can provide an extensive amount of information about complex metabolic pathways, yet much of the significance of the non–wild-type variants remains unknown. The study of variants found in cancer cells is an exploding field assisting in the selection of antineoplastic drugs; however, it is out of the scope of this article. This review focuses on the germline mutations in human DNA affecting drug absorption, distribution, metabolism, and excretion. Many of these mutations are single-nucleotide polymorphisms that can affect the enzyme expression in the individual. This can lead to either overexpression commonly referred to as “ultra-rapid” metabolizers or underexpression referred to as “intermediate” and “poor” metabolizers.

Interpreting Pharmacogenomic Results

Pharmacogenomic results are uniquely identified by the star allele (*), which is not otherwise used in the field of genetics. The text representation of normal or “wild-type” variant status is generally, but not always, *1/*1.1 As new alleles are discovered, they are numbered sequentially *2, *3, and so forth. The Human Cytochrome P450 Allele Nomenclature Database ( http://www.cypalleles.ki.se/) and the Database of Genomic Variants ( http://dgv.tcag.ca/dgv/app/home) serve as repository databases for new allele discoveries. For interpretation and practical application, the PharmGKB website ( www.PharmGKB.org) is a comprehensive database for providers.

These phenotypes can help guide drug and dose selection. Other common phenotypes refer to the presence or absence of a variant, such as with the human leukocyte antigen (HLA) variants. The presence of certain HLA variants is associated with increased risk of serious and even fatal side effects from the use of affected medications.

Several other factors must be considered when deciding how to apply the pharmacogenomic information. The pharmacologic properties of the medication are extremely important. For example, a prodrug, a medication that must be converted by the body to the active form of the drug, will have the opposite effect in the setting of a poor or ultra-rapid metabolizer status. If the active form of the medication is ingested and is processed via a pathway that has limited enzyme expression (eg, poor metabolizer) the likely result is that the patient will experience exaggerated side effects as the drug lingers in the body longer and is not broken down to inactive or less active metabolites. However, if that same patient is given a prodrug that is metabolized via the same pathway, the patient will likely experience little to no therapeutic effect because the drug is being converted too slowly or not at all to the active formulation. Therefore, the application of pharmacogenomic information is tailored to the drug being considered for use and is not a “one size fits all.” Most drug metabolic pathways are complex and are not controlled by a single enzyme. In some cases, the metabolites can be shunted to lesser used pathways, either resulting in no discernable effect on the patient, in amplified toxicity, or in some cases a complete lack of response. Additionally, existing drug-drug, drug-supplement, and drug-food interactions can be amplified or diminished by these pharmacogenomic phenotypes. As always, the patient's disease state, organ function, sex, smoking status, and diet can also play a role in drug metabolism that is unrelated to the pharmacogenomics. Variables specific to infants and children include maturation of renal function, hepatic clearance, and other developmental factors such as gastrointestinal absorption rates. CYP450 enzyme maturation is an important consideration in determining the extent of pharmacogenetic variant effect on drug metabolism.2

Understanding the Limitations and Benefits of Pharmacogenomic Testing

During both the drug development and postmarketing analysis phases, it becomes clear that some patients will experience severe adverse drug reactions and others will fail to respond at all to the population-derived standard dose. These adverse reactions are expressly distinct from harm caused by medication errors or lack of proper adherence to the drug. In 2000, The Institute of Medicine cited over 2 million voluntarily reported adverse drug reactions in the United States per year resulting in approximately 100,000 deaths and at a cost of $29 billion annually.3 It is well known that adverse drug reactions are infrequently reported and often go undetected, making the actual number likely much greater. The clinical application of pharmacogenomics allows providers to more accurately predict who may be at higher risk for developing an adverse reaction if exposed to a drug or drug class.4 Adverse drug reactions directly increase health care costs and decrease quality of life. Therefore, the goal of pharmacogenomics is to increase general usage through conclusively showing impact on clinical outcomes.5

Several drug variant associations can and should be used in clinical practice today. For example, pre-emptive testing for HLA-B*5701 is required by the US Food and Drug Administration (FDA) black box warning prior to the initiation of abacavir due to the risk of developing a life-threatening rash.6 Screening is strongly encouraged prior to initiating other medications such as carbamazepine and the thiopurines. Other testing is required prior to use of medications targeted to correct specific defects, such as ivacaftor in patients with cystic fibrosis and related cystic fibrosis transmembrane conductance regulator variants. See Table 1 for a partial list of actionable drug-gene pairs focused on medications used frequently in pediatrics. For a complete list of actionable genotypes and the associated medications, please refer to the website: PharmGKB.org

Partial List of Actionable Drug-Gene Pairs

Table 1:

Partial List of Actionable Drug-Gene Pairs

Pharmacogenomics can help pediatricians and families make safer decisions about medication usage with the goal of matching the right drug in the right dose to the right patient to achieve the most benefit with minimal side effects. However, testing that provides information about a single-disease state when the pathway affects more medication classes or usage of nonstandard laboratory processes can be detrimental, as can overstating the effect a genotype may have. Guidance with application on only one disease state or with questionable testing practices can cause more harm than good. Interpretations that focus only on a single condition, such as attention-deficit/hyperactivity disorder, and ignoring the influence that genotype may have on other medication classes can result in patient harm. Of note, it is well documented that patients who have had pharmacogenomics testing are more compliant with their medications, even if the results were unremarkable or “normal.”7

When Does Testing Make Sense?

Clearly testing is indicated when required by the FDA for safety or efficacy prior to starting a medication. Testing can be considered for patients with an extensive history of either nonresponse or serious adverse effects. The results can help guide future therapeutic choices as well as possibly give patients and families an explanation for historic responses. The impact on patients and families of providing an explanation for an adverse reaction, even for historical events, should not be understated.

Although the study of pharmacogenomics is not new, we are just beginning to understand the complex relationship between genetics, drug metabolism, and individual response. There are new discoveries published every day and soon a patient's pharmacogenomics profile will undoubtedly be an integral piece of routine prescribing.

References

  1. Sim SC, Ingelmann-Sundberg M. The human cytochrome P450 (CYP) allele nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Hum Genomics. 2010;4(4):278–281. doi:10.1186/1479-7364-4-4-278 [CrossRef]
  2. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349:1157–1167. doi:. doi:10.1056/NEJMra035092 [CrossRef]
  3. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy of Sciences; 2000.
  4. Sikka R, Magauran B, Ulrich A, Shannon M. Bench to bedside: pharmacogenomics, adverse drug interactions, and the cytochrome P450 system. Acad Emerg Med. 2005;12(12):1227–1235. doi:. doi:10.1197/j.aem.2005.06.027 [CrossRef]
  5. Beitelshees AL, Veenstra DL. Evolving research and stakeholder perspectives on pharmacogenomics. JAMA. 2011;306(11):1252–1253. doi:. doi:10.1001/jama.2011.1343 [CrossRef]
  6. Atazanavir [package insert]. Piscataway, NJ: Camber Pharmaceuticals, Inc; 1998.
  7. Haga SB, LaPointe NM. The potential impact of pharmacogenetic testing on medication adherence. Pharmacogenetics J. 2013;13(6):481–483. doi:. doi:10.1038/tpj.2013.33 [CrossRef]
  8. Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Therap. 2012;92(4):414–417. doi:. doi:10.1038/clpt.2012.96 [CrossRef]

Partial List of Actionable Drug-Gene Pairs

Drug Gene/Variant Adverse Reaction Action
Abacavir HLA-B*57:01 Risk of life-threatening rash, Stevens Johnson syndrome Pre-emptively test, avoid if positive for the variant
Atazanavir UGT1A1 Increased risk of jaundice Avoid if positive for the variant
Carbamazepine HLA-B*15:02, HLA-A*31:01 Risk of life-threatening rash, Stevens Johnson syndrome Avoid if positive for the variant
Codeine CYP2D6 Risk of toxicity, risk of nonresponse Avoidance dependent upon variant
Ivacaftor CFTR Risk of nonresponse Pre-emptively test, initiate medication if variant approved
Ondansetron CYP2D6 Risk of nonresponse Avoidance dependent upon variant
Phenytoin CYP2C9, HLA-B*15:02 Risk of toxicity, risk of life threatening rash, Stevens Johnson syndrome Dose decrease or avoidance dependent upon variant
Rasburicase G6PD Increased risk of hemolysis Avoid if positive for the variant
Selective serotonin reuptake inhibitors CYP2C19 Risk of toxicity, risk of nonresponse Dose decrease, increase, or alternative drug selection dependent upon specific variant
Tacrolimus CYP3A5 Risk of nonresponse Dose increase dependent upon specific variant
Thiopurines (6-mercaptopurine, thioguanine, azathioprine) TPMT Risk of life-threatening neutropenia Dose decrease dependent upon specific variant
Tricyclic antidepressants CYP2D6, CYP2C19 Risk of toxicity, risk of nonresponse Dose decrease or increase dependent upon specific variant
Voriconazole CYP2C19 Risk of nonresponse Dose increase dependent upon specific variant
Authors

Shannon Manzi, PharmD, BCPPS, is the Director, Clinical Pharmacogenomics Service, Division of Genetics & Genomics, and the Manager, Intensive Care Unit and Emergency Services, Department of Pharmacy, Boston Children's Hospital; and an Assistant Professor of Pediatrics, Harvard Medical School.

Address correspondence to Shannon Manzi, PharmD, BCPPS, Department of Pharmacy, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115; email: Shannon.manzi@childrens.harvard.edu.

Disclosure: Shannon Manzi is a consultant for Global Gene, Inc, a company that seeks to provide pharmacogenomics testing and interpretation for physicians and other health care providers.

10.3928/19382359-20180429-01

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