Erik Hefti, PharmD, MS

Personalized medicine is a healthcare approach that utilizes various technologies to accurately separate patients into specific groups for more precise treatment. Genomics is a key technology being leveraged by some healthcare providers to assist in making treatment decisions.

Currently, there are multiple applications of personalized medicine in clinical practice, including assisting in medication selection. Unfortunately, a personalized medicine knowledge gap currently exists between many healthcare providers in the United States, and around the globe.

Personalized medicine is a relatively recent development in the healthcare sphere. Incorporating genomics into clinical decision making has only been feasible with the advent of improved technologies allowing cost-effective genomic analysis. Genomic diagnostic and decision-making tools are being developed at a higher rate now than ever before. Unfortunately, didactic coursework in healthcare curricula that prepares healthcare professionals to utilize personalized medicine has been slow to catch up. This has left many practicing healthcare professionals in the workforce without formal training in personalized medicine, which may be hampering adoption of personalized medicine.

One obvious solution to addressing this personalized medicine knowledge gap in healthcare professionals involves incorporating more robust didactic, and experiential education into the curriculums of medical, nursing, pharmacy, and related programs. Formal classes in pharmacogenomics have been widely implemented in many pharmacy programs in the United States; however, there are still challenges that face expanding classroom education.

It may be difficult to find room in the curriculums of many programs that train healthcare professionals. Furthermore, personalized medicine is a large, somewhat diffuse field of study that encompasses diverse disciplines. It can be difficult to compress the many aspects of personalized medicine into a single course that adequately trains healthcare professionals to confidently utilize these tools in practice. Another problem with simply expanding didactic training is that it does not address the healthcare professionals currently in the workforce. These individuals will not benefit from expanding formal training in personalized medicine. Furthermore, these professionals can often make the best use of precision medicine, given their experience and clinical knowledge.  

So, how can we address this knowledge gap? Some possibilities include a combination of pre- and post-graduate education in addition to employing a multidisciplinary approach to patient care. It is critical that personalized medicine topics be presented in healthcare curricula. While there may not be time to delve into all topics comprehensively in the classroom, foundational instruction in personalized medicine will allow for more efficient learning in a practice setting, as needed. More post-graduate continuing education programs could be developed for healthcare professionals in disciplines that currently utilize personalized medicine. Another potential approach would be developing programs designed for working/practicing professionals to become more formally educated in personalized medicine. These include certificate, and degree programs that can be taken in a distance-learning format.

For some clinicians currently practicing, robust clinical decision support software that incorporates personalized medicine may also assist in filling the knowledge gap by quickly providing evidence-based recommendations with respect to incorporating personalized medicine into care.

 Also, incorporating healthcare professionals with more developed knowledge in a specific aspect of personalized medicine (such as a pharmacist trained in pharmacogenomics) into a multidisciplinary clinical team can further leverage the strengths of each member to best treat the patient.

 Discussing the evidence, and approaches within a multidisciplinary team can build a better knowledge base of participating members, and ultimately improve patient care.

The education gap in personalized medicine may be a potential barrier to broad implementation currently; however, this gap may shrink with more robust developments in the field combined with more robust pre- and post-graduate education opportunities for healthcare professionals.

Haiech J, Kilhoffer M-C. Personalized medicine and education: the challenge. 

Taber KAJ, Dickinson BD. Pharmacogenomic knowledge gaps and educational resource needs among physicians in selected specialties. 

Pharmacogenomics and personalized medicine

Hinderer M, Boeker M, Wagner SA, et al. The experience of physicians in pharmacogenomic clinical decision support within eight German university hospitals. 

Rao US, Mayhew SL, Rao PS. Strategies for implementation of an effective pharmacogenomics program in pharmacy education. 

Hinderer M, Boeker M, Wagner SA, et al. Integrating clinical decision support systems for pharmacogenomic testing into clinical routine-a scoping review of designs of user-system interactions in recent system development. 

BMC medical informatics and decision making

Hinderer M, Boerries M, Boeker M, et al. Implementing Pharmacogenomic Clinical Decision Support into German Hospitals. 

Studies in health technology and informatics

Articles

A personalized medicine knowledge gap currently exists between many healthcare providers in the United States, and around the globe.

What to Do About the Personalized Medicine Knowledge Gap

Human leukocyte antigens (HLAs) are genes that encode cell-surface proteins that are critical for distinguishing one’s own cells and proteins from foreign cells or proteins. HLAs are necessary for the proper function of our immune system; however, certain variants of HLAs (alleles) are associated with severe drug toxicities. As more research on these variants becomes available and pharmacogenomics testing becomes more widely available, it will be important for pharmacists to be familiar with clinically-significant HLA alleles and their associated drug toxicities. The FDA maintains a list of relevant pharmacogenomic biomarkers, which includes HLA alleles associated with adverse drug reactions (ADRs)

. Below is a summary of some select clinically significant HLA alleles and drugs that are present on the FDA’s list of pharmacogenomic biomarkers.

o   HLA-B*5701 (abacavir) - The allele HLA-B*5701 is generally found at a higher frequency in Han Chinese populations and is associated with abacavir hypersensitivity reactions. Abacavir is a nucleoside reverse transcriptase inhibitor used to treat 

. These hypersensitivity reactions can include severe fever, rash, 

 upset, or respiratory issues. It is recommended that genetic testing be performed on all potential patients prior to initiation of abacavir.

o   HLA-B*1502, HLA-A*3101 (carbamazepine) - Carbamazepine is an anticonvulsant that has multiple indications, including seizure disorders and neuropathic 

. The allele HLA-B*1502 is present at a higher frequency in East Asian populations and is associated with the development of Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) when taking carbamazepine. It is recommended that patients of Asian descent be tested for the presence of this allele prior to beginning carbamazepine therapy.

The allele HLA-A*3101 is associated with an increased risk of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) when taking carbamazepine.

Many regulatory bodies recommend testing for HLA-A*3101 status in carbamazepine-naive patients.

o   HLA-DQA1*0201, HLA-DRB1*0701 (lapatinib) - The alleles HLA-DQA1*0201 and HLADRB1*0701 are both alleles that are associated with increased risk of hepatotoxicity in patients being treated with lapatinib, a signal transduction inhibitor used to treat certain patients with breast cancer.

Currently, these biomarkers are listed in the package insert as being correlated with hepatotoxicity, but testing recommendations are not clear. It is generally recommended that liver function tests are monitored regardless of HLA status.

There are ongoing studies examining the presence of HLA alleles and drug toxicities. The list of clinically-significant HLA biomarkers will likely increase as more research becomes available. Currently, there are other HLA-ADR associations not listed on the FDA’s list of biomarkers. One example is HLA-B*5801, which has been associated with severe cutaneous reactions following allopurinol treatment

. HLA variants are being explored as potential biomarkers for clozapine-induced agranulocytosis.

 As genomic testing becomes more available, it will be important for health care professionals and patients to be aware of clinically significant HLA alleles that can impact pharmacotherapy.  

1. FDA. Table of Pharmacogenomic Biomarkers in Drug Labeling. 2015; 

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

2. Ma JD, Lee KC, Kuo GM. HLA-B*5701 testing to predict abacavir hypersensitivity. 

3. Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens—Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. 

4. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and Carbamazepine-induced hypersensitivity reactions in Europeans. 

5. Dean L. Carbamazepine Therapy and HLA Genotypes. 2015; 

http://www.ncbi.nlm.nih.gov/books/NBK321445/

6. Spraggs CF, Budde LR, Briley LP, et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. 

7. Schaid DJ, Spraggs CF, McDonnell SK, et al. Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury. 

8. Tassaneeyakul W, Jantararoungtong T, Chen P, et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. 

9. Goldstein JI, Jarskog LF, Hilliard C, et al. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. 

Patients that express certain human leukocyte variants are at risk for adverse drug events when taking certain medications. 

Human Leukocyte Antigen and Adverse Drug Events: What Pharmacists Should Know

Mango fruits are ubiquitous at supermarkets around the nation and enjoyed by many. What may come as a surprise to many is that the rind of fresh mangos contains allergens similar to those found in poison ivy or poison oak.

For some, consuming mango products can cause oral dermatitis and erythema. This is a rare, but characterized, reaction that impacts a small number of people. The severity of this reaction varies from person to person; however, it can be mild enough that individuals may choose to self-treat. Pharmacists should be aware of this rare allergy and some potential treatment approaches.

Allergies to mango can be dangerous, so it is best to recommend seeing a physician if it's the first time they are experiencing the reaction. Treating nonanaphylactic reactions (dermatitis, skin or mucosal irritation, erythema) is similar to treating urticaria (hives) or cutaneous puritic reactions. Topical or oral steroid treatment for 3-5 days have been reported to be used for mango-associated dermatitis. Over-the-counter first-generation antihistamines have also been reported as effective. Symptoms will generally resolve within a week with or without treatment. If they do not, further medical attention may be required.

Avoiding eating or touching fresh mangos is the best way to prevent this reaction in those affected. Using gloves or protective equipment when handling is necessary would be advised. The sap, which contains a high concentration of the irritating compounds, found mostly in the skin of the fresh fruit, should be avoided. Canned, preserved, and processed mango products can still contain mango allergens but not necessarily the irritating sap.

Those who suffer from mango-associated dematitis should exhibit cautions when handling any naturally-derived mango product.

Many pharmacists practice in an environment where people are exposed to mango fruits. Understanding the potential for this fruit to cause dermatitis can help a pharmacist better advise patients how to proceed if they develop adverse cutaneous reaction following mango exposure.

1. Hershko K, Weinberg I, Ingber A. Exploring the mango—poison ivy connection: the riddle of discriminative plant dermatitis. 

2. Weinstein S, Bassiri?Tehrani S, Cohen DE. Allergic contact dermatitis to mango flesh. 

3. Dube M, Zunker K, Neidhart S, Carle R, Steinhart H, Paschke A. Effect of technological processing on the allergenicity of mangoes (Mangifera indica L.). 

Mango fruits are ubiquitous at supermarkets around the nation and enjoyed by many. 

Mango-Associated Dermatitis: What are the Treatment Options?

Down syndrome (DS), also known as trisomy 21, is the most common cause of mental retardation.

DS is caused by the presence of an additional 21st chromosome in affected individuals.Patients with DS, especially children, are often on medications to treat various comorbidities that are frequently present.

 Unfortunately, their unique genetic condition can impact drug therapy in certain circumstances.

 Differential drug disposition in patients with DS has been reported with select medications, although the clinical significance is often unclear. There are non-CYP drug metabolizing enzymes and other factors that can impact drug disposition that are located on the 21st chromosome. Altered drug metabolizing enzyme expression combined with physiologic factors unique to the condition can lead to patients with DS exhibiting an altered response to some medications.

This is highlighted when talking about certain cytotoxic chemotherapy agents.Pediatric patients with DS have an elevated risk for certain cancers, such as acute myeloid leukemia and acute lymphoblastic leukemia. Patients with DS and leukemia are often treated with cytotoxic chemotherapy regimens, which generally exhibit excellent efficacy.

Unfortunately, patients with DS often display increased rates of adverse effects from the chemotherapy. The proposed reasons for elevated adverse drug reactions range from an underlying cellular pro-oxidative state to altered pharmacokinetics of specific agents such as methotrexate or thioguanine.

 There are few prospective reports that investigate the impact of chemotherapy in patients with DS; however, the reports that do exist often suggest treating hematological malignancies with reduced doses of select cytotoxic chemotherapeutics combined with close monitoring for toxicity. Pharmacists that are responsible for monitoring or coordinating chemotherapy regimens should be aware that patients with DS may require adjusted dosing to avoid severe toxicities.

Besides cancer, patients with DS also have a higher likelihood of developing Alzheimer’s-like dementia as they age. Treating Alzheimer’s remains difficult in patients with and without DS. Medications like donepezil have been used to treat patients with DS and dementia with some success.

 It has also been reported that patients with DS had higher plasma concentration of donepezil compared with patients without DS after receiving the same dose. These patients with the higher plasma concentrations of donepezil also exhibited higher rates of adverse reactions to the drug. Pharmacists should be aware that patients with DS may require non-traditional dosing to achieve better therapeutic efficacy with donepezil.

There are multiple non-clinical reports that suggest altered disposition can occur in DS with many different drugs. Most of these reports are not clinically substantiated; however, they do indicate the potential impact that DS can have on pharmacotherapy. DS is a condition that has a large physiologic effect and may impact drug disposition. Pharmacists should take DS status into account when evaluating medication appropriateness and safety by consulting the most current scientific literature available. This may be especially important when evaluating the safety of cytotoxic chemotherapy regimens.

1. Kerins G, Petrovic K, Bruder MB, Gruman C. Medical conditions and medication use in adults with Down syndrome: a descriptive analysis. 

Down's syndrome, research and practice: the journal of the Sarah Duffen Centre / University of Portsmouth

2. Hefti E, Blanco JG. Pharmacotherapeutic considerations for individuals with Down Syndrome. 

Pharmacotherapy: J Hum Pharm Drug Therapy.

doi: 10.1002/phar.1880. [Epub ahead of print]

3. Zwaan CM, Kaspers GJ, Pieters R, et al. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. 

4. Hefti E, Blanco JG. Pharmacokinetics of Chemotherapeutic Drugs in Pediatric Patients With Down Syndrome and Leukemia. 

5. Hefti E, Blanco JG. Anthracycline-Related Cardiotoxicity in Patients with Acute Myeloid Leukemia and Down Syndrome: A Literature Review. 

6. Lott IT, Osann K, Doran E, Nelson L. Down syndrome and Alzheimer disease: response to donepezil. 

7. Kondoh T, Nakashima M, Sasaki H, Moriuchi H. Pharmacokinetics of donepezil in Down syndrome. 

Down syndrome results in a massive genetic imbalance in those who have the disorder. 

Drug Therapy and Down Syndrome

Recently, in New York State, the governor announced a push to deliver free tuition to public colleges and universities for students from families making under $125,000 per year. This echoes what many have been calling for nationally: tuition-free public colleges and universities. What is not being widely discussed is the potential impact this may have on private pharmacy schools.

Many in private education are concerned that incentivizing public institutions alone will reduce enrollment in the private institutions over time to the point that they may be forced to close. This leads some to wonder about how that will impact private pharmacy education. In Buffalo, NY alone, there are 4 pharmacy schools within a 2-hour drive; 3 are private. Two are associated with private, liberal arts colleges. If tuition-free public undergraduate education becomes available in New York State, or even nationwide, these private pharmacy schools may be impacted. Lower undergraduate enrollment may mean higher tuition for all students at these schools.

Recently, there has been a persistent worry among many regarding the large number of pharmacy schools that are opening across the country that may result in a flooded job market, lowered salaries, and increased job scarcity. It is possible that increased economic stress on private institutions may limit the rapid proliferation of pharmacy schools. The opposite is also possible. As pharmacy schools can bring in more students and tuition dollars, many private institutions may consider opening pharmacy schools as a hedge for the tough economic times ahead.

Obviously, this is all simply conjecture as no formal plans have been solidified in New York State or beyond. It is clear that tuition-free public undergraduate education is a hot topic of conversation and, if implemented, could have a dramatic effect on higher education in general.

Pharmacists in and out of academia would likely be impacted by these changes as well. We should be discussing the ramifications of free public undergraduate institutions and contribute to the larger political conversation to ensure pharmacy education is positively impacted in these times of change. 

Recently, in New York State, the governor announced a push to deliver free tuition to public colleges and universities for students from families making under $125,000 per year. 

How Free Tuition Could Change the Pharmacy Education Landscape 

Celiac disease is an autoimmune disorder that renders those affected with an intolerance to gluten, a protein found in many common grains. It occurs in approximately 1% of the population of the United States and Europe.

People with celiac disease that ingest gluten generally experience an inflammatory reaction, manifested as gastrointestinal upset, diarrhea, and abdominal distension. Celiac disease is also associated with other chronic conditions, such as anemias and malabsorption of some critical vitamins. Alterations of the gastrointestinal tract, rates of gastric emptying, and gastric pH are responsible for altered vitamin and mineral absorption.

Intestinal CYP3A4 levels may also be disrupted, which may have implications in first-pass metabolism for some drugs that are substrates for this drug metabolizing enzyme.

This has led some to investigate the potential impact of celiac disease on drug absorption. This would be of interest to pharmacists since altered drug absorption can have pharmacokinetic consequences and has the potential to impact overall drug therapy.

A comprehensive review on this topic was published in 2013 by Tran et al.The review considered absorption studies in subjects with celiac disease, and the authors summarized the literature available on a handful of drugs, including acetaminophen, aspirin, propranolol, levothyroxine, methyldopa, and some antibiotics.They reported that many studies had conflicting results. Some reports show an altered gastrointestinal environment and a significant difference in drug absorption in patients with celiac disease. Other reports did not show any absorption differences between those with and without the disease. It was noted that many of the studies considered for their analysis had small sample sizes and were not well powered. The authors concluded that there is the potential for altered drug absorption and that healthcare professionals should be cautious when initiating drug therapy.

Another review on the topic of celiac disease and the potential impact on cardiovascular drug absorption was published in 2014. This review considered many of the same medications previously explored by Tran et al, with a focus on cardiovascular agents. The authors also expressed concern that many cardiovascular drugs may have altered absorption in celiac disease, but there are few published studies that are convincing enough for concrete clinical decision making. The authors also stressed the need for more studies that consider patients with celiac disease, as well as caution when initiating cardiovascular pharmacotherapeutic regimens.

Based on the research available, it is clear that patients with celiac disease can exhibit altered absorption of many different substrates. Unfortunately, altered drug absorption and disposition are not well studied in this population. It is likely that future studies will elucidate any impact celiac disease has on drug disposition, as this disorder has been getting more attention in recent years. There is some preliminary evidence suggesting that celiac disease may alter drug absorption, but the degree and prevalence of this has yet to be confirmed with large prospective studies. Pharmacists should be cautious when making therapeutic recommendations for patients with celiac disease and consult the available literature when possible.

Increased monitoring for efficacy and adverse effects is advisable when starting a new medication regimen in patients with celiac disease.

1.  Catassi C, Gatti S, Fasano A. The new epidemiology of celiac disease. 

2.  Perri F, Pastore M, Zicolella A, Annese V, Quitadamo M, Andriulli A. Gastric emptying of solids is delayed in celiac disease and normalizes after gluten withdrawal. 

3.  Caruso R, Pallone F, Stasi E, Romeo S, Monteleone G. Appropriate nutrient supplementation in celiac disease. 

4.  Lang CC, Brown RM, Kinirons MT, et al. Decreased intestinal CYP3A in celiac disease: Reversal after successful gluten?free diet: A potential source of interindividual variability in first?pass drug metabolism. 

5.  Tran TH, Smith C, Mangione RA. Drug absorption in celiac disease. Amer J Health-System Pharm. 2013;24.

6.  Wang I, Hopper I. Celiac Disease and Drug Absorption: Implications for Cardiovascular Therapeutics. 

Celiac disease is a disorder that renders sufferers intolerant to gluten. 