While research from as far back as the 1960’s indicates that genetic variations are directly responsible for different medication responses, only recently have the reduced costs of testing made the benefits of pharmacogenomics (PGx) available to many patients. Incorporating PGx insights into the consideration of medication options results in more safe, efficacious, and cost-effective drug therapies that improve patient care by reducing the need for “trial-and-error” periods.

The understanding of and support for PGx is expanding. The National Institutes of Health (NIH) maintains a list of clinical trials involving PGx1 and works to maximize the benefits of pharmacogenomics research for individuals and society2. The U.S. Food and Drug Administration (FDA) also maintains a list of around 200 biomarkers for genetic variations that are included in different sections of drug labels3.

It is important to view this information in the proper context to best serve the patient. While the list of clinical trials and pharmacogenetic tests is continually expanding, many medications are not yet associated with clinically useful guidance. The science is evolving and will require clinical resources that are already set up to monitor and interpret rapid advancements.

Pharmacogenomics: Tailoring drug therapies for improved outcomes

White Paper

Daniel S. Streetman, PharmD, MSKandace Schuft, PharmD

In both 20144 and 20165, the Journal of the Medical Library Association (JMLA) identified Lexicomp® as the strongest online resource for point-of-care clinical use of PGx information.

Case in Point: The Effect of Gene Variability on Pain ManagementWith both 11 percent of the adult U.S. population reporting some form of chronic pain6 and continuing concerns about opioid-related death, controlling misuse of the opioids prescribed to mitigate that pain is a major challenge for patient care teams. An increasingly viable method of ensuring that opioids are not overprescribed or abused is to consider how the patient’s genetic variations may affect opioid response.

A noteworthy example of applying PGx insights when prescribing pain medication is the association of the CYP2D6 genotype and the metabolism of opioids. Gene variations can affect the metabolism of some pain medications, such as codeine, resulting in lower or higher drug concentrations. This variability leads to patients being categorized as poor, intermediate, normal, or ultra-rapid metabolizers. Approximately 5-10 percent of patients have been found to have a deletion of the CYP2D6 gene (no activity), and between 1-2 percent and more than 20 percent of patients have multiple copies, or increased activity7.

Although testing for CYP2D6 genotypes as a means of choosing a dose for any of these compounds is not yet considered standard practice, Clinical Pharmacogenetics Implementation Consortium (CPIC)8 guidelines provide CYP2D6 genotype-based recommendations for codeine use, along with additional recommendations for tramadol, oxycodone and hydrocodone, based on the available clinical evidence. Limited data is also available that guides the use of non-opioids, including tricyclic antidepressants.

When identifying patients who may potentially benefit from genomic screening before prescribing pain treatments, clinicians may want to consider the following factors:

• History: Has the patient tried and failed many therapies in the past?

• Polypharmacy: Multiple medications combined can create drug-drug and drug-gene interactions.

• Age: 50-75 percent of the elderly population experiences chronic pain; analysis of Medicare prescription plans reveals that only one-third of those covered by the plans had access to treatments other than opioids due to the low cost of opioids.

• Condition: Cancer patients and those suffering from post-surgical pain have been shown to struggle with longer-term management of pain.

By consulting the “CYP2D6 - Codeine Monograph” in Lexicomp, both physicians and pharmacists can be made aware of special considerations they should keep in mind when faced with this drug-gene pairing, including recommendations on when to perform genetic testing, alternate therapies to consider, and in-depth discussion of the gene on metabolization of codeine.

Lexicomp is the Leading Clinical PGx ResourceRelationships between genetic variations and drug response are continually investigated by researchers, and such information is added to the Lexicomp database together with clear, meticulous guidelines for application. Lexicomp provides a foundation for all clinicians who will be called on to integrate this rapidly-expanding genomic knowledge into the management of drug therapy, including the following data and content:

• links to additional information about drug or gene

• recommendations regarding need for genetic testing

• unique evidence ratings that assess both the clinical validity and utility of each gene-drug association

Clinicians with access to Lexicomp will be well-positioned to make use of emerging research on pharmacogenomics both today and in the future. Lexicomp PGx monographs describe both specific drug-gene pairs and genetic variations. Each monograph contains information to help clinicians understand the implications of using the drug to treat a patient with the genetic variation in question.

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Case in Point: The Effect of Racial Heritage on Drug DispositionThe impact of race/ethnicity on drug disposition is understood to varying degrees by clinicians when making treatment decisions. Ongoing research is increasing the availability of information for clinicians to consider; in a 2015 review9, researchers stated that approximately 20 percent of the new drugs approved in the past several years have known racial/ethnic differences in disposition.

One of the most well-known examples of race-specific pharmacogenetic responses involves G6PD deficiency, which is more common in individuals of African or Mediterranean heritage. The G6PD deficiency has been associated with a high risk for

hemolysis with potentially significant consequences when these individuals are exposed to any of dozens of specific medications, including many antimalarial medications, phenazopyridine, nitrofurantoin, and other medications .

Two other less common relationships that are reflected in approved drug labeling include:

• Risk for severe hypersensitivity reactions due to carbamazepine in patients of Asian heritage, associated with presence of HLA-B*15:0210.

• Risk for death due to excessive conversion of codeine into morphine, which is thought to vary by ethnicity, but is associated with the presence of multiple functional copies of the gene encoding CYP2D611.

Summary

As more medication responses are matched to genetic variations, it is important to use a clinical resource that recognizes the value of an evolving science that may permit more rapid identification of safer and more effective drug therapies. Lexicomp can serve as a first resource to find information and references on many genes and their interactions with common drugs, including those discussed above. The Pharmacogenomics field in applicable Lexicomp monographs also discusses management of treatment and ongoing research to monitor.

Lexicomp drug information and UpToDate clinical recommendations are developed by a global network of in-house and external clinical and pharmacy experts. With these resources aligned for care, your teams can enhance communication, reduce inconsistent practices, and connect clinical and pharmacy decisions to increase effectiveness.

Daniel S. Streetman, PharmD, MS, is the manager of referential content in the Metabolism, Interactions, & Genomics group with Clinical Effectiveness from Wolters Kluwer, Health. He completed a research fellowship in clinical pharmacology, with an emphasis in pharmacogenomics, at Bassett Healthcare in Cooperstown, NY, and was a clinical faculty member at the University of Michigan for several years prior to joining Wolters Kluwer. Dr. Streetman continues to maintain an academic relationship with several schools, lecturing on pharmacogenomics and other topics.

Kandace Schuft, PharmD, is Senior Clinical Content Specialist - Pharmacogenomics with Clinical Effectiveness from Wolters Kluwer, Health. She earned her Doctor of Pharmacy and Bachelor of Arts degrees from the University of Minnesota and completed a post-graduate pharmacy practice residency and pharmacogenomics certification program.

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About the authors:

US/CAN: tel 1.855.633.0577 | All other countries: tel +1 330.650.6506Please visit www.wolterskluwercdi.com for more information.

©2018 Wolters Kluwer Clinical Drug Information, Inc. and its affiliates and/or licensors. All rights reserved.11.18 | 06018

1 NIH Website. https://clinicaltrials.gov/search/term=pharmacogenomics+OR+pharmacogenetics. Accessed October 2018.

2 NIH Website. https://www.nigms.nih.gov/education/Pages/factsheet-pharmacogenomics.aspx. Content updated October 2017. Accessed October 2018.

3 Table of Pharmacogenomic Biomarkers in Drug Labeling. FDA Website. https://www.fda.gov/drugs/scienceresearch/ucm572698.htm. Accessed October 2018.

4 Vaughan KTL, Scolaro KL, Anksorus HN, Roederer MW. An evaluation of pharmacogenomic information provided by five common drug information resources. JMLA. 2014;102(1):47-51. doi:10.3163/1536-5050.102.1.009. http://doi.org/10.3163/1536-5050.102.1.009. Accessed October 2018.

5 Chang JS, Pham D-A, Dang MT, Lu Y, VanOsdol S, Shin J. Evaluation of popular drug information resources on clinically useful and actionable pharmacogenomic information. JMLA. 2016;104(1):58-61. doi:10.3163/1536-5050.104.1.009. http://doi.org/10.3163/1536-5050.104.1.009. Accessed October 2018.

6 Nahin RL. Estimates of Pain Prevalence and Severity in Adults: United States, 2012. J Pain. 2015;16(8):769-780. doi:10.1016/j.jpain.2015.05.002. https://dx.doi.org/10.1016%2Fj.jpain.2015.05.002. Accessed October 2018.

7 Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014 Update. Clinical Pharmacology and Therapeutics. 2014;95(4):376-382. doi:10.1038/clpt.2013.254. http://doi.org/10.1038/clpt.2013.254. Accessed October 2018.

8 Caudle KE, Klein TE, Hoffman JM, et al. Incorporation of Pharmacogenomics into Routine Clinical Practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process. Curr Drug Metab. 2014;15(2):209-217. doi:10.2174/1389200215666140130124910. http://doi.org/10.2174/1389200215666140130124910. Accessed October 2018.

9 Ramamoorthy A, Pacanowski MA, Bull J, Zhang L. Racial/ethnic differences in drug disposition and response: review of recently approved drugs. Clin Pharmacol Ther. 2015 Mar;97(3):263-73. https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.61. Accessed October 2018.

10 Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT. (2004) Medical genetics: a marker for Stevens-Johnson syndrome. Nature 428:486. http://dx.doi.org/10.1038/428486a. Accessed October 2018.

11 Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, Carleton B, Hayden MR, Madadi P, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. Pediatrics. 2012;129(5):e1343. Epub 2012 Apr 9. https://www.ncbi.nlm.nih.gov/pubmed/22492761. Accessed October 2018.