The Role of the Pediatric Pharmacist in Personalized Medicine and Clinical Pharmacogenomics for Children

Abstract

With the initiatives by the National Institutes of Health and the Food and Drug Administration, pharmacogenomics has now moved from the laboratory to the patient bedside. Over 100 drug-products now contain pharmacogenomic information as part of their labeling. Many of these are commonly used in the pediatric population. Direct-to-consumer genetic test kits also require intervention and guidance from healthcare professionals. This increased trend towards personalized medicine mandates that healthcare professionals develop a working knowledge about pharmacogenomics and its application towards patient care. Because pharmacogenomic testing can provide patient-specific predictors for response to and safety of medications, pharmacists are positioned to play an active role in pharmacogenomic testing, clinical interpretation of results, and recommendations for individualization of drug therapy. Opportunities for pharmacists exist in both inpatient and outpatient settings, such as pharmacist-managed clinical pharmacogenomics consultation services and educating patients and families about pharmacogenomic testing. In addition to clinical roles, pharmacists may also be involved in genetically-influenced drug discovery and development. Given the potential for genetic and age-dependent factors to influence drug selection and dosing, pediatric pharmacists should be involved in the development of dosing recommendations and interprofessional practice guidelines regarding pharmacogenomic testing in pediatric patients. Opportunities to become knowledgeable and competent in pharmacogenomics span from coursework as part of the pharmacy curriculum to postgraduate education (e.g., residencies, fellowships, continuing education). However, there exists a need for additional postgraduate learning opportunities for practicing pharmacists. As a result, the Pediatric Pharmacy Advocacy Group (PPAG) acknowledges a need for increased education of both student and practicing pharmacists, with consideration of special patient populations, such as infants and children. PPAG endorses and advocates for the involvement of pediatric pharmacists in pharmacogenomic testing and in using those results to provide safe and effective medication use in pediatric patients of all ages. Additionally, PPAG strongly encourages pediatric pharmacists to take responsibility for educating patients and their families about the importance of pharmacogenomic testing and its role in the safe and effective use of medications.

INTRODUCTION

Patient response to drug therapy is highly variable, and adverse events are often unpredictable. Some patients may have significant adverse reactions to very small doses of a particular drug, whereas others may require a substantially higher dose of the same drug to achieve an equivalent therapeutic response. Over the last decade, a dramatic increase has occurred in our understanding of how drug response may be influenced by variations in a single gene (pharmacogenetics), gene networks, and/or the entire genome (pharmacogenomics). With the completion of the Human Genome (2003) and International HapMap (2007) Projects, the information and tools necessary to identify important gene-response associations are now widely available. Increasing availability of genetic tests in clinical laboratories and decreasing analytical costs are also facilitating the application of pharmacogenomic testing in patient care. The promise of “personalized medicine” is therefore steadily progressing toward becoming a reality. It is clear that genomics will play an increasingly important role in drug development, regulation, and prescribing in the near future. For pharmacists, genomics is also proving to be a powerful clinical tool that, when used to develop individualized treatment plans for a specific patient, may ultimately increase the likelihood of selecting the right drug at the right dose for the right patient and/or of reducing the number of adverse drug events.

The clinical implementation of pharmacogenomics has admittedly been slower than anticipated after completion of the Human Genome Project. However, advancing pharmacogenomics into clinical practice remains a national healthcare priority. At the forefront of this effort are federal organizations such as the National Institutes of Health (NIH), which created and provides funding for a collaborative research network dedicated to the discovery of clinically relevant gene-response associations (the Pharmacogenomics Research Network or PGRN). As a result of research conducted by members of the PGRN, the Pharmacogenomics Research Knowledge Base (PharmGKB), a leading, publically available database in the field of pharmacogenomics, was created. The Clinical Pharmacogenetics Implementation Consortium (CPIC), an extension of the PGRN, also was formed in 2009 to facilitate development of specific guidelines that can be used for clinical interpretation of genetic-testing results that can be used to adjust medications or to change drug selection. The first of these guidelines, which provides dosing recommendations for the thiopurine drugs based on the thiopurine methyltransferase (TPMT) genotype, were published in March 2011.¹

The Food and Drug Administration (FDA) has also provided guidance to facilitate the translation of pharmacogenomic discoveries into clinical tools that can be used to improve patient care. In 2004, the FDA launched its Critical Path Initiative and identified genomics as one of the areas of scientific discovery that should be applied during drug development. The following year, they released a document for pharmaceutical manufacturers that encourages voluntary submission of pharmacogenomic data obtained during the drug-development process. The Pharmaceutical Research and Manufacturers of America subsequently released their own white paper in 2008 recommending that drug-metabolizing enzyme and transporter genotyping be incorporated into the drug-development process.² The FDA has also instituted a focused initiative to improve the quality of product labeling and, when relevant, to include pharmacogenomic information. As a direct result of these initiatives, more than 120 drug-product labels now contain pharmacogenomic information, and many of these drugs (e.g., mercaptopurine, warfarin, atomoxetine) are commonly used in children. The FDA is also actively evaluating direct-to-consumer genetic test kits that, if marketed, would be directly available to patients or their caregivers for purchase in the community.

With the rapid advancement of clinical pharmacogenomics has come the recognition that professional schools must increase the amount of genomics-focused instruction in their curricula, and this has been echoed by various organizations, including the International Society of Pharmacogenomics. Increased education and training of healthcare professionals in the discipline of pharmacogenomics could also help support the Institute of Medicine platform of adverse drug reaction prevention by facilitating the increased application of personalized medicine.³ Deans of Education at health professional schools have therefore been called to incorporate pharmacogenomics into the core professional curricula.⁴

PPAG agrees with previous statements by the American Pharmacists Association,⁵ the American College of Clinical Pharmacy,⁶ and the American Association of Colleges of Pharmacy,⁷ which promote the role of pharmacists in pharmacogenomic testing, clinical interpretation, and education. PPAG endorses the development of core competencies and/or certification courses in addition to curricular content for colleges of pharmacy to ensure that pharmacists have a foundation of knowledge in pharmacogenomics and are prepared appropriately to manage personalized pharmacotherapy. PPAG also believes that the application of pharmacogenomics in children presents unique technical, ethical, and interpretive challenges that require the expertise of pharmacists with specialized training in pediatrics.

This position statement is intended to serve as an official endorsement from PPAG supporting the key role of pediatric pharmacists in clinical interpretation and application of pharmacogenomic testing related to pediatric pharmacotherapy. This statement provides a rationale as to why pediatric pharmacists should be involved in pharmacogenomics, identifies potential roles that pediatric pharmacists might play, and provides suggestions for how we as pharmacists can prepare for the integration of pharmacogenomics into our clinical practice.

WHY SHOULD PEDIATRIC PHARMACISTS BE INVOLVED IN PHARMACOGENOMICS?

Pharmacists are publicly recognized as the content experts for drug therapy. Our role on the medical team has been well established and has led to improved patient outcomes. Clinical interventions are based on patient variability and response, and pharmacists make it their primary goal to provide safe and effective drug therapy to their patients. Therapeutic drug monitoring of narrow-therapeutic-index medications is a good example of pharmacists demonstrating this role on the team. Pharmacogenomics provides patient-specific predictors for response and safety. Predicting the likelihood of efficacy or potential toxicities, based on pharmacogenetic information, will help to improve therapy decisions. Clinical applicability of genetic testing may prevent adverse events and improve patient outcomes, despite the ethical considerations and potential implications of lifelong genetic-data availability. Pharmacists must play a key role in interpretation of clinical pharmacogenomic tests. Pharmacists are equipped with specialized drug knowledge and can therefore serve as a valuable resource with respect to dose adjustments and/or drug selection based on the results of genetic tests. A concentrated professional education in medicinal chemistry, pharmacokinetics, pharmacology, and therapeutics provides the basis of our role as medication experts. Incorporation of pharmacogenomics into this specialized background will allow us to provide more appropriate recommendations, to improve therapy, and potentially to avoid adverse outcomes. This becomes increasingly important when evaluating the pediatric patient in whom genetic and disease-state influences on pharmacokinetics and pharmacodynamics must be interpreted in the context of underlying developmental changes. The specialized knowledge and expertise of a pediatrics-trained pharmacist is therefore essential for correct interpretation of genetic test results in the pediatric population.

WHAT POTENTIAL ROLES CAN PEDIATRIC PHARMACISTS PLAY IN PHARMACOGENOMICS?

The roles that pharmacists will ultimately play in clinical pharmacogenomics have yet to be defined. Our profession and practice specialty therefore have significant opportunities to advocate for and to establish the role of pediatric pharmacists in pharmacogenomics. The most obvious role for pharmacists in clinical pharmacogenomics is clinical interpretation of test results. Given our unique knowledge of drug disposition and action in children, we are the only healthcare professionals able to estimate treatment response and provide drug-selection and/or dosing recommendations based on the integration of genotype data with other patient-specific factors. This is particularly true in the pediatric population, in which results of genetic tests must be considered in the context of normal developmental changes in the dose-exposure-response relation.

Pharmacists are also ideally positioned to help establish the clinical utility and economic benefit of specific pharmacogenomic tests through written documentation of their recommendations and collection of outcomes data. Similarly, pharmacists can work with physicians to develop standard protocols and/or to establish collaborative practice agreements that facilitate pharmacist-driven ordering of pharmacogenomic tests. Development of pharmacist-managed clinical pharmacogenomics consultation services is also a possibility that has already been successfully implemented in several pediatric academic medical centers.⁸ Existing pharmacokinetic and/or therapeutic drug monitoring services can serve as the platform for the introduction of pharmacist-driven clinical pharmacogenomic testing.

Pharmacists also can provide education to patients and their families about pharmacogenomic testing, particularly in the ambulatory and community pediatric settings. They are readily accessible to prescribers and patients, making them a valuable resource for drug-therapy or genetic-testing recommendations. Direct-to-consumer advertising of pharmacogenomic tests is becoming increasingly common, and pharmacists can have an active role in ensuring that parents understand the validity, implications, and limitations of pharmacogenomic tests. The number of off-the-shelf genetic tests is also expected to increase over the next few years, and pharmacists can serve as a valuable resource for patients with respect to sample collection, results interpretation, and resource availability for pre- and posttest genetic counseling.

In addition to the expanded clinical opportunities, pharmacogenomics offers some novel prospects for pharmacists, particularly in the areas of discovery and development.⁹ Pharmacists can readily identify drugs whose response may be influenced by genetic factors and can develop a list of drug candidates that should be evaluated in gene-response association studies. Pharmacists can also help to define the criteria used to standardize drug response (i.e., phenotype) and can identify candidate genes for further study based on their knowledge of receptors and/or biologic pathways involved in drug response. Additionally, pharmacists with specialized training in pediatrics are able to determine whether a gene-response association is likely to be significant in children of different ages and whether data from genomic studies in adults can be extrapolated to the pediatric population. Most important, pediatric pharmacists must be involved in the development of dosing recommendations and multidisciplinary practice guidelines for the application of pharmacogenomic testing in infants and children.

WHAT OPPORTUNITIES ARE CURRENTLY AVAILABLE FOR PHARMACISTS TO BECOME MORE KNOWLEDGEABLE AND COMPETENT IN PHARMACOGENOMICS, AND WHAT ARE THE NEEDS FOR THE FUTURE?

Pediatric pharmacy practice is no exception to the impact of pharmacogenomics and personalized medicine. It is therefore imperative that future pediatric pharmacists gain a solid foundation in this area as part of their training and professional development. Since 2001, the American Association of Colleges of Pharmacy has encouraged inclusion of pharmacogenetics and pharmacogenomics in the Doctor of Pharmacy (PharmD) curriculum. This resulted in the proposed “Competencies in Pharmacogenetics and Pharmacogenomics” that currently resonates as part of Accreditation Council for Pharmacy Education (ACPE) standards.¹⁰ The number of Colleges or Schools of Pharmacy that have added pharmacogenomics to pharmacy education has increased dramatically (39% to 97.1%), according to a survey of Colleges or Schools of Pharmacy. Despite this increase, however, pharmacogenomic instruction and advanced practice experiences at most schools of pharmacy are inadequate, especially in areas related to pediatric-specific topics.^11–13

Opportunities for residency and fellowship training specific to pharmacogenomics are limited, with only two fellowship programs established nationally and only one dedicated to pediatrics. Pharmacogenomics has also not been widely integrated into PGY1 and PGY2 residency programs, and this should be a goal for postgraduate training programs. Beyond residency training, the Pharmacogenomics Education Program (UC San Diego), supported by a grant from the Centers for Disease Control and Prevention, is available for pharmacist professional development. The program provides evidence-based pharmacogenomic continuing education to all healthcare professionals, free of charge, on several areas (none pediatrics specific), such as asthma, cardiology, oncology, and psychiatry.¹⁴ Also noteworthy, some hospital systems have developed continuing education for their pharmacists. The Children's Hospital of Wisconsin developed an online and livemodule course based on objectives from the National Coalition for Health Professional Education in Genetics guidelines.¹⁵ The online module includes introductory concepts on genetics and pharmacogenomics, particularly related to antiepileptic medications, and is a required competency for all pharmacists to provide pharmacogenomic services at the hospital.¹⁶ St. Jude's Children's Research Hospital has also developed educational programs for their pharmacists to complete before providing pharmacogenomic consultation, and this may serve as an example for other institutions to follow.⁸

RECOMMENDATIONS

PPAG endorses the involvement of pediatric pharmacists in pharmacogenomic testing and believes that pharmacists should be the healthcare professionals responsible for interpreting and applying pharmacogenomic test results as they relate to pediatric pharmacotherapy. PPAG also strongly encourages pharmacists to take responsibility for educating patients and their families about pharmacogenomic testing, especially in the community setting, where genetic test kits are likely to be directly available to patients or caregivers in the near future. PPAG acknowledges a need for increased education of both students and practicing pharmacists, which should include key concepts in the basic sciences of pharmacogenetics and pharmacogenomics, but also should incorporate clinical applications, such as interpretation of test results, with consideration of special patient populations, such as infants and children. PPAG believes that pharmacogenomics is an emerging discipline that will become increasingly important in pediatric pharmacotherapy. As genotype-based dosing recommendations and practice guidelines are developed, the need for pediatric pharmacists trained in this discipline will become essential.

ABBREVIATIONS

FDA

Food and Drug Administration

NIH

National Institutes of Health

PPAG

Pediatric Pharmacy Advocacy Group

PGRN

Pharmacogenomics Research Network