Jerika Lam, PharmD

More than 90% of patients harbor DNA variants that could affect their response to a medication.

Each individual has a unique genetic makeup that affects drug absorption, efficacy, metabolism, and response. Pharmacogenomics (PGx) addresses how an individual’s DNA influences the response to a medication. With recent advances in health sciences, we can predict a patient’s phenotype, such as metabolic activity, from the genotype, such as genetic variants, to prevent serious adverse effects (AEs) and therapeutic failure or to optimize treatment efficacy. 

Determining the presence of a certain genotype, such as thiopurine methyltransferase for patients treated with thiopurine drugs

 or HLA-B*57:01 for patients receiving abacavir,

 can help prevent potentially fatal adverse reactions. Furthermore, because enzymes are critical in the metabolism of many drugs, understanding the enzyme phenotypes is crucial to predicting adverse drug events (ADEs) or therapeutic outcomes. Many drug-metabolizing enzymes and drug transporters are subject to genetic polymorphisms. 

Specifically, Cytochrome P450 (CYP) enzymes, such as CYP2C9, CYP2C19, and CYP2D6, are highly polymorphic and are associated with distinct phenotypes ranging from highly increased activity to no activity. This translates to individuals having intermediate, normal, rapid, poor, or ultrarapid metabolism of drugs. 

A poor metabolizer of an enzyme that inactivates a drug may be at higher risk of AEs with standard dosing, because of supratherapeutic active drug concentration in the serum. By contrast, a poor metabolizer of an enzyme responsible for activating a drug may not get the therapeutic benefit of the drug, because of the subtherapeutic concentration of the active metabolites, whereas an ultrarapid metabolizer of the same enzyme may be at increased risk of AEs of the active compound (see the clinical example below). 

Thus, pharmacists need to consider many factors and use clear guidance on predicting a phenotype from a genotype to intervene optimally based on the specific drug-gene interaction.

Predicting a phenotype from a genotype is becoming increasingly challenging, considering the ever-growing knowledge in PGx. There are PGx guidelines available from various consortia and regulatory agencies, including the FDA, to help translate the phenotype from genotype to guide intervention. The most well-accepted guidelines in the United States are provided by the Clinical Pharmacogenetic Implementation Consortium (CPIC).

The CPIC evaluates evidence and provides specific recommendations regarding whether to alter dosing or avoid a drug. Pharmacists also need guidance on which PGx test to use based on the genes and allele coverage provided in each test.

 The Association of Molecular Pathology provides such guidance on allele selection for individual gene testing.

As medication experts with adequate PGx training, pharmacists are best suited to identify patients at risk and use appropriate PGx tests to evaluate patients’ medications across multiple specialties, including cardiology, mental health, pain management, and oncology, to ensure patient safety and optimize care.

MG, a 42-year-old Caucasian woman with recurrent major depressive disorder, takes a maximum dose of escitalopram 20 mg/day without benefit. She was recently switched from paroxetine (a CYP2D6 substrate and mechanism-based inhibitor) to escitalopram (a CYP2C19 substrate), because of a potential drug interaction with her metoprolol (a CYP2D6 substrate). 

For the past 15 years, her dose of paroxetine was maintained at a low dose of 10 mg/day, with good efficacy for her major depression. Her PGx test results show that she is a poor metabolizer of CYP2D6 and an ultrarapid metabolizer of CYP2C19.

MG’s PGx test results explain why she is not responding to the maximum dose of escitalopram. MG is expected to have subtherapeutic escitalopram concentration as a CYP2C19 ultrarapid metabolizer. On the other hand, paroxetine at a low daily dose of 10 mg worked well for MG, because the paroxetine concentration was elevated, because she is a CYP2D6 poor metabolizer.

Escitalopram should be avoided, and paroxetine should be reduced to 50% of the standard dose to avoid side effects for MG, according to CPIC recommendations.

Other treatments to adjust or avoid include citalopram, fluvoxamine, sertraline, and venlafaxine. In this case, 10 mg of paroxetine once a day with continued monitoring may be appropriate for MG. Bradycardia related to metoprolol should be monitored, and a lower dose of metoprolol should be considered, because the metabolism of metoprolol is impaired in this patient (CYP2D6 poor metabolizer), in addition to paroxetine being a CYP2D6 mechanism-based inhibitor.

The translation of a genotype into a phenotype for a drug considering inter-subject variability in drug pharmacokinetics or pharmacodynamics is complex.

 The complexity increases further when several genes are involved in the pharmacology of a drug or when multiple drugs affect the same enzyme, such as competing substrates, inducers, or inhibitor effects, as in MG’s case.

Coadministration of drugs that modulate drug-metabolizing enzyme activities, whether competing substrates, inducers, inhibitors, or mechanism-based inhibitors, can lead to a phenomenon known as phenoconversion.

Phenoconversion occurs when a patient’s observed phenotype differs from the genotype-predicted phenotype. The mismatch between the genotype-based prediction of CYP drug metabolism and the real-time capacity of an individual to metabolize drugs (ie, a phenotype) can be because of nongenetic factors, such as concomitant medications, disease, the environment, and food. The effect of phenoconversion may also differ across age, genotype, race, and sex.

Consequently, interpreting PGx results in patients with multiple chronic diseases and polypharmacy requires the intervention of drug experts. This is where pharmacists’ unique training can provide expert clinical guidance.

Undoubtedly, PGx offers an excellent opportunity for personalized medicine. However, no test, including the PGx tests, should be ordered unless the ordering authority is able to interpret the final clinical results, develop a meaningful diagnosis, intervention, or prognosis, and implement an appropriate action plan with the results of such test.

We think that the time has come for pharmacists to be recognized as the experts and owners for ordering and interpreting PGx test results.

On February 28, 2022, a federal bipartisan legislation called the Right Drug Dose Now Act was introduced in Congress to address drug-gene interactions and enable the use of PGx testing to ensure that patients receive the most appropriate prescription medications based on their genetic makeups. 

The bill will also create an educational campaign to prevent ADEs, improve electronic health record systems to ensure that health care providers are alerted to drug-gene interactions, update the US Department of Health and Human Services’ National Action Plan for Adverse Drug Events Prevention. Furthermore, the bill will allocate additional funding to the Genomic Community Resources program at the National Institutes of Health to integrate PGx testing into patient care.

Similar legislation was introduced in the California senate on February 12, 2022, which amended Senate Bill 1191, known as the Utilizing Pharmacogenomics to Greatly Reduce Adverse Drug Events Act, to include PGx testing as a covered benefit under Medi-Cal insurance. The bill defines PGx testing as genetic panel testing by a laboratory with specified accreditation and licensing to identify how an individual’s genetics may affect the efficacy, safety, and toxicity of medications. 

The bill would cover the benefit of a medication under Medi-Cal if it is approved or considered for use in treating the beneficiary’s condition, known to have a drug-gene or drug-drug-gene interaction that is shown to be clinically actionable and ordered by an enrolled Medi-Cal clinician or pharmacist within their scope of practice.

Pharmacists are best equipped to implement PGx and support health care decision-making to help patients benefit from personalized medicine. By interpreting PGx test results, pharmacists could recognize the risk of ADEs or treatment failure and provide alternatives based on patients’ genetics. Legislation is also increasingly supporting PGx implementation by allowing pharmacists to take the leadership role in PGx implementation and reimbursing for their services in this field.

1. Ji Y, Skierka JM, Blommel JH, et al. Preemptive pharmacogenomic testing for precision medicine: a comprehensive analysis of five actionable pharmacogenomic genes using next-generation DNA sequencing and a customized CYP2D6 genotyping cascade. 

2016;18(3):438-445. doi:10.1016/j.jmoldx.2016.01.003

2. Relling MV, Gardner EE, Sandborn WJ, et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. 

2011;89(3):387-391. doi:10.1038/clpt.2013.4

3. Lam JT. Infectious Diseases Pharmacogenomics. In: Lam JT GMA, Shah S, eds. 

Pharmacogenomics: A Primer for Clinicians.

4. Relling MV, Klein TE. CPIC: clinical pharmacogenetics implementation consortium of the pharmacogenomics research network. 

2011;89(3):464-467. doi:10.1038/clpt.2010.279

5. Sayer M, Duche A, Nguyen TJT, et al. Clinical implications of combinatorial pharmacogenomic tests based on cytochrome P450 variant selection. 

2021;12(1628). doi:10.3389/fgene.2021.719671

6. Pratt VM, Cavallari LH, Del Tredici AL, et al. Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists. 

7. Pratt VM, Del Tredici AL, Hachad H, et al. Recommendations for clinical CYP2C19 genotyping allele selection: a report of the Association for Molecular Pathology. 

2018;20(3):269-276. doi:10.1016/j.jmoldx.2018.01.011

8. Hamann K, Daut, RA, Gutierrez MA. Psychiatry and Neurology Pharmacogenomics. In: Lam JT GMA, Shah S , eds. 

9. DPWG: Dutch Pharmacogenetics Working Group DPW. PharmGKB. Accessed April 23, 2022.

10. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. 

2008;83(2):234-242. doi:10.1038/sj.clpt.6100406

11. Kirchheiner J. CYP2D6 phenotype prediction from genotype: which system is the best? 

2008;83(2):225-227. doi:10.1038/sj.clpt.6100455

12. Hicks JK, Swen JJ, Gaedigk A. Challenges in CYP2D6 phenotype assignment from genotype data: a critical assessment and call for standardization. 

2014;15(2):218-232. doi:10.2174/1389200215666140202215316

13. Cicali EJ, Elchynski AL, Cook KJ, et al. How to integrate CYP2D6 phenoconversion into clinical pharmacogenetics: a tutorial. 

2021;110(3):677-687. doi:10.1002/cpt.2354

14. Deodhar M, Al Rihani SB, Arwood MJ, et al. Mechanisms of CYP450 inhibition: understanding drug-drug interactions due to mechanism-based inhibition in clinical practice. 

2020;12(9). doi:10.3390/pharmaceutics12090846

15. Del Toro-Pagan NM, Matos A, Thacker D, Turgeon J, Amin NS, Michaud V. Pharmacist-led medication evaluation considering pharmacogenomics and drug-induced phenoconversion in the treatment of multiple comorbidities: a case report. 

16. Pizzolato K, Thacker D, Del Toro-Pagán N, et al. Integrating pharmacogenomic results and drug-induced phenoconversion concepts while conducting a medication safety review process.

17. Shah RR, Smith RL. Addressing phenoconversion: the Achilles' heel of personalized medicine. 

2015;79(2):222-240. doi:10.1111/bcp.12441

18. Sikaris KA. Enhancing the clinical value of medical laboratory testing. 

19. Lee DW, Neumann PJ, Rizzo JA. Understanding the medical and nonmedical value of diagnostic testing. 

2010;13(2):310-314. doi:10.1111/j.1524-4733.2009.00597.x

20. Emmer, Swalwell introduce legislation to prevent adverse drug effects. Tom Emmer. News release. February 28, 2022. Accessed April 26, 2022. https://emmer.house.gov/2022/2/emmer-swalwell-introduce-legislation-to-prevent-adverse-drug-effects

21. Medi-Cal: pharmacogenomic testing. In: Bill CS, ed. 

2022. Accessed April 26, 2022. https://leginfo.legislature.ca.gov/faces/billTextClient.xhtml?bill_id=202120220SB1191

Articles

They should consider many factors and use clear guidance on predicting phenotypes from genotypes to intervene optimally based on specific drug-gene interactions.

Pharmacists Play Role in Pharmacogenomics Clinical Services

Among the many treatments for diseases, vaccines are the safest and most cost-effective form of preventive medicine in the United States. Despite a rise in vaccination rates among young adults between 1993 and 2013, a persistently low uptake of routinely recommended immunizations remains among adults 50 years or older.

 Except for modest increases in tetanus, diphtheria, and pertussis vaccination for adults 19 years or older and herpes zoster (shingles) vaccination among those 60 years or older, adult vaccination coverage did not improve from 2013 to 2014. The CDC reports that a low trend for influenza, human papilloma virus (HPV), pneumococcal, hepatitis B (for health care providers), and herpes zoster vaccinations continues to persist among adults.

 These poor vaccination rates could be attributed to gaps in insurance coverage, personal beliefs, and disparities in access to vaccines. As a result, the burden of vaccine-preventable diseases translates into significant social, public health, and economic costs within our society.

At present, 8 vaccines have age-only recommendations by the CDC to protect adults against 11 diseases (Table 1

). An additional 5 vaccines can be used to protect adults with specific medical conditions or activities. The CDC delineates 5 age groups for adult vaccination: 19 to 21 years, 22 to 26 years, 27 to 59 years, 60 to 64 years, and ≥65 years. Also available from the CDC is an immunization table that lists medical conditions and activities that serve as indications or contraindications to adult vaccines.

 Because of more effective childhood immunization programs, diseases such as measles, rubella, diphtheria, tetanus, and pertussis are rare among adults 19 years or older.

 However, reports of limited adult cases of measles, mumps, or pertussis have emerged in recent years in areas of low vaccine uptake.

In 2015, there were 14.1 million cases of vaccine- preventable diseases attributable to unvaccinated adults. Of the total economic burden of approximately $9 billion due to direct costs and productivity losses from vaccine-preventable diseases, lack of vaccination was responsible for $7.1 billion.

 displays the burden of some common vaccine-preventable diseases from 2012 to 2016.

 It is clear that case rates have declined more than 90% for all major diseases since their peak years. However, there have been some disturbing trends with measles and pertussis in children and mumps in college-aged adults.

Measles and mumps are viral infections that are highly contagious via the respiratory route. Although the vaccine for both of these diseases is contained in the measles, mumps, and rubella (MMR) vaccine and childhood immunization rates are high, outbreaks continue. In the United States, measles cases start as imported disease, mostly from travelers to nations with low vaccination rates. Thus, it is essential that individuals in the United States who travel to other countries receive 2 doses of MMR before departing. Mumps has also experienced a resurgence in both travelers to Europe and college campuses in the United States. In many of these settings, 2-dose MMR vaccination is high, but even the small failure rate associated with the vaccine can allow outbreaks to occur.

According to the CDC, fewer than 50% of adults chose to receive the flu vaccine in the 2015-2016 season. More effort is required to ensure that individuals who see their health care providers during the flu season receive the vaccination. In addition, health care providers are strongly advised to receive annual influenza vaccinations.

 Over several years, pharmacists have continued to lead other medical professions in getting their flu shot.

 If not vaccinated, they may serve as a source of influenza virus transmission to vulnerable patients.

Herpes zoster has been increasing since 1992, and 1 out every 3 individuals in the United States will develop it during their lifetime. However, only 28% get vaccinated.

 Reasons for the low herpes zoster vaccination rates include in some cases the high cost of the vaccine, challenges to stocking the vaccine (requires freezer storage), billing issues, and out-of-pocket costs.

 Because a great proportion of all herpes zoster vaccine is distributed to pharmacies, and pharmacists in all 50 states can administer the vaccine, it is imperative that pharmacists take a proactive role in zoster vaccination.

For the unvaccinated adult group 65 years or older, the incidence of influenza and pneumococcal disease accounts for the greatest burden of disease,

 as both influenza and pneumococcal disease can result in hospitalization and death. However, unvaccinated individuals in younger age groups account for a higher percentage of cases of vaccine-preventable diseases: 85% of adults aged 19 to 49 years, 81% of adults aged 50 to 64 years, and 56% of adults 65 years or older.

Patient barriers to vaccination include lack of awareness of the need for the vaccine, disbelief that receiving the vaccine will be helpful, low education level, busy schedules and competing demands, and lack of recommendations by a health care provider.

 The last barrier centers on provider issues: research shows that some physicians do not believe vaccines are effective; therefore, they do not recommend vaccination to their patients, do not stock the vaccines, and fail to act as proponents for adult vaccination.

Recently, the CDC and the National Vaccine Advisory Committee proposed 4 essential components for improving vaccination rates: (1) assess immunization status, (2) recommend (make strong recommendations for needed vaccines), (3) administer or refer (stock and administer needed vaccines or refer to a provider who can), and (4) document (using immunization information systems or immunization registries).

 Research has shown that individuals who are steadfast on refusing vaccination are still open to listening and even getting vaccinated when a health care provider makes a strong recommendation.

Now that pharmacists have expanded authority to vaccinate in every state, they need to become proactive vaccinators by identifying and making strong recommendations for all patients. Doing so will help reduce the burden of influenza, HPV, pneumococcal disease, herpes zoster, and other vaccine-preventable diseases.

Jerika Lam, PharmD, is assistant professor, Department of Pharmacy Practice, Chapman University School of Pharmacy, Irvine, California.

Jeff Goad, PharmD, MPH, is professor and chair, Department of Pharmacy Practice, Chapman University School of Pharmacy, Irvine, California.

CDC. Adult vaccination coverage — United States, 2010. 

Chun GJ, Sautter JM, Patterson BJ, McGhan WF. Diffusion of pharmacy-based influenza vaccination over time in the United States. 

. 2016;106(6):1099-1100. doi: 10.2105/AJPH.2016.303142.

CDC. Flu vaccination coverage: United States, 2013-2014 influenza season. CDC website. cdc.gov/flu/fluvaxview/coverage-1314estimates.htm. Published September 2014. Updated January 28, 2016. Accessed February 24, 2017.

Williams WW, Lu PJ, O’Halloran A, et al; CDC. Surveillance of vaccination coverage among adult populations—United States, 2014. 

. 2016;65(1):1-36. doi: 10.15585/mmwr.ss6501a1.

CDC. Recommended immunization schedule for adults aged 19 years or older, United States, 2017. CDC website. cdc.gov/vaccines/schedules/downloads/adult/ adult-combined-schedule.pdf. Published February 2017. Accessed February 24, 2017.

McLaughlin JM, McGinnis JJ, Tan L, Mercatante A, Fortuna J. Estimated human and economic burden of four major adult vaccine-preventable diseases in the United States, 2013. 

. 2015;36(4):259-273. doi: 10.1007/s10935- 015-0394-3.

Helmecke MR, Elmendorf SL, Kent DL, Pauze DK, Pauze DR. Measles investigation: a moving target. Am J Infect Control. 2014;42(8):911-915. doi: 10.1016/j. ajic.2014.04.024.

Ozawa S, Portnoy A, Getaneh H, et al. Modeling the economic burden of adult vaccine-preventable diseases in the United States. 

. 2016;35(11):2124-2132. doi: 10.1377/hlthaff.2016.0462.

CDC. Notifiable diseases and mortality tables. CDC website. cdc.gov/mmwr/ mmwr_nd/nd_data_tables.html. Published January 2017. Updated January 30, 2017. Accessed February 24, 2017.

CDC. Update: mumps outbreak—New York and New Jersey, June 2009-January 2010. 

CDC. Flu vaccination coverage, United States, 2015-16 influenza season. CDC website. cdc.gov/flu/fluvaxview/coverage-1516estimates.htm. Published September 2016. Updated September 29, 2016. Accessed February 24, 2017.

Black CL, Yue X, Ball SW, et al. Influenza vaccination coverage among health care personnel—United States, 2015-16 influenza season. 

. 2016;65(38):1026-1031. doi: 10.15585/mmwr.mm6538a2.

CDC. Shingles surveillance. CDC website. cdc.gov/shingles/surveillance. html. Updated August 19, 2016. Accessed February 24, 2017.

Weycker D, Sato R, Strutton D, Edelsberg J, Atwood M, Jackson LA. Public health and economic impact of 13-valent pneumococcal conjugate vaccine in US adults aged ≥50 years. 

. 2012;30(36):5437-5444. doi: 10.1016/j. vaccine.2012.05.076.

Williams WW, Lu PJ, Lindley MC, Kennedy ED, Singleton JA; CDC. Influenza vaccination coverage among adults—National Health Interview Survey, United States, 2008-09 influenza season. 

Lau D, Hu J, Majumdar SR, Storie DA, Rees SE, Johnson JA. Interventions to improve influenza and pneumococcal vaccination rates among community dwelling adults: a systematic review and meta-analysis. 

. 2012;10(6):538- 546. doi: 10.1370/afm.1405.

Zimmerman RK, Santibanez TA, Fine MJ, et al. Barriers and facilitators of pneumococcal vaccination among the elderly. 

Zimmerman RK, Santibanez TA, Janosky JE, et al. What affects influenza vaccination rates among older patients? An analysis from inner-city, suburban, rural, and veterans affairs practices. 

CDC. Influenza and pneumococcal vaccination levels among persons aged ≥65 years—United States, 2001. 

Kimura AC, Nguyen CN, Higa JI, Hurwitz EL, Vugia DJ. The effectiveness of vaccine day and educational interventions on influenza vaccine coverage among health care workers at long-term care facilities. 

. 2007;97(4):684-690. doi: 10.2105/AJPH.2005.082073.

Nichol KL, Zimmerman R. Generalist and subspecialist physicians’ knowledge, attitudes, and practices regarding influenza and pneumococcal vaccinations for elderly and other high-risk patients: a nationwide survey.

Silverman M, Terry MA, Zimmerman RK, Nutini JF, Ricci EM. Tailoring interventions: understanding medical practice culture. 

. 2004;19(2):47-76. doi: 10.1023/B.JCCG.0000027845.23006.e8.

CDC. Standards for adult immunization practice. CDC website. cdc.gov/ vaccines/hcp/adults/for-practice/standards. Updated May 2, 2016. Accessed February 24, 2017.

Nichol KL, MacDonald R, Hauge M. Factors associated with influenza and pneumococcal vaccination behavior among high-risk adults. 

Among the many treatments for diseases, vaccines are the safest and most cost-effective form of preventive medicine in the United States.