Theranostics in Primary Care

Pharmacogenomics Tests and Beyond

Gillian Bartlett; Jumana Antoun; Nathalie K Zgheib

Expert Rev Mol Diagn. 2012;12(8):841-855.

Beyond PGx

In addition to PGx, theranostics applications include the use of genomics platforms with, for example, nutrition (nutrigenomics), development of vaccines (vaccinomics) and diagnostics (nanodiagnostics). Although these subfields of theranostics are relatively new and limited in application to specialized care, it is hoped that by drawing on the lessons from PGx, primary care should eventually play a greater role for these 'omics'.^[80]

Nutrigenomics

Nutrigenomics is the science that describes the interplay between bioactive chemicals from foods with gene expression through epigenetic alterations.^[81] Thus, nutrigenomics addresses the genetic basis of the variability in an individual's response to diet. Additionally, genome health nutrigenomics is the science that studies the optimal dietary intake to preserve the genome and avoid DNA damage and mutations.^[82]

One example of nutrigenomics is the association between the apolipoprotein E locus and interaction of habitual alcohol consumption and plasma low-density lipoprotein (LPL)-C and high-density lipoprotein (HDL)-C. For instance, moderate habitual alcohol consumption was shown to be potentially beneficial for E2 carriers by decreasing their LDL; however, it could be harmful to E4 carriers as it could raise LDL and dampen down the expected increase in HDL.^[83] Other clinical applications for nutrigenomics include the potential prevention of chronic diseases such as obesity, diabetes and cardiovascular diseases; for example, individuals with certain genotypes were shown to have an increased risk of becoming obese if they increase their carbohydrate intake to more than 49% of the total calorie consumption.^[81] However, these results need to be confirmed.

Although nutritional genomics was first described in the beginnings of the 1990s and it was projected that in the next century, products will be marketed as the appropriate diet to a certain genotype,^[84] its progress has been slow and its clinical utility in practice is still lacking.^[83] Some of the challenges facing the field of nutrigenomics include the complex diet–gene interactions, lack of knowledge of the specific genes that cause chronic diseases, and lack of reliable tools for the assessment of nutrient intake.^[81] As a result, nutrigenomics may not be at a stage to be included in primary-care theranostics.

Vaccinomics

Vaccinomics takes into account the following two concepts: one, different immunologic responses exist for different genotypes, and two, different persons have different risks to develop the disease being prevented. Vaccinomics research is currently focused on the better understanding of complex polymorphic HLA system. Some alleles were identified to be associated with nonresponse to specific vaccines and others were suggested to be responsible for the febrile seizures after measles mumps and rubella vaccination. Hence, parents whose children are carriers of certain alleles might elect not to vaccinate their children based on the side-effect profile of the vaccine.^[85]

One of the most important challenges facing vaccinomics is its conflict with the public health model of prevention that entitles a universal acceptability and distribution of the vaccine.^[85] In addition, applications of vaccinomics would require more testing and thus more time and effort, while most of the currently available classical vaccines are highly efficacious, hence, personalized vaccination would be targeting only 5% of the population.^[85] Despite these challenges, vaccinomics is still expected to lead the way to new techniques to develop the next generation vaccines whereby there will be no need to isolate the incriminating virus but rather rely on the immune system; this is promising in the development of vaccines against moving targets, such as viruses.^[86,87]

Nanodiagnostics

Also in the field of theranostics, nongenomic platforms, such as nanoparticles, are gaining interest from the research community whereby very small particles are designed to be carriers of contrast agents or drugs to diagnose or treat targeted cancer cells respectively.^[88,89] This emerging technology, termed nanodiagnostics, involves very specialized knowledge and skills and is hence expected to be led by radiology and oncology specialists. Nevertheless, the PCP ought to be aware of its existence and its challenges in order to counsel potential patients or research subjects. Current issues to be resolved include lack of data concerning safety, efficiency, pharmacokinetics and biocompatibility.^[90,91]

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Table 1. Nonrepresentative list of germline pharmacogenetic tests relevant to primary care.
Protein	Abbreviation	Drug or drug class	Effect with poor metabolizer phenotype
*Drug-metabolizing enzymes*
Cytochrome P450 2C9	CYP2C9	Warfarin Tolbutamide	Bleeding Hypoglycemia
Cytochrome P450 2C19	CYP2C19	Diazepam Clopidogrel	Prolonged sedation Poor response
Cytochrome P450 2D6	CYP2D6	Antidepressants Codeine Tamoxifen	Increased toxicity Inadequate pain relief Poor overall survival
*Drug transporters*
Solute carrier organic anion 1B1	SLCO1B1	Simvastatin	Increased myopathy
ATP-binding cassette B1	ABCB1	Digoxin	Increased toxicity
*Drug targets*
β2 adrenergic receptor	ADRB2	β₂ agonists	Decreased bronchodilation
Arachidonate 5 lipoxygenase	ALOX 5	Leukotriene receptor antagonists	Decreased effect
Human leukocyte antigen-B	HLA-B	Abacavir	Hypersensitivity

These data are compiled from several articles^26,45,53,55 and from the relevant US FDA drug labels.

Table 2. Examples of challenges to the clinical translation of pharmacogenomics in primary care, moving forward and further needs.
Challenges	Moving forward	Further needs
Ethical legal and social implications	Commentaries and guidelines from several bodies, GINA in the USA	More policies against genetic discrimination
Lack of clinical utility	CDC ACCE framework Pharmacoeconomic studies	More pharmacoeconomic studies Unified guidelines for pharmacoeconomic studies
Lack of clinical implementation guidelines	PGx research groups and regulatory bodies reviewing evidence and writing guidelines	More reviews Consistency among the different guidelines Practical guidelines
Need for education	PGx educational guidelines Updates of some medical schools and residency curricula	Education on practical issues beyond the basic principles of PGx

GINA: Genetic Information Nondiscrimination Act of 2008; PGx: Pharmacogenomics.

Table 3. Resources where updated pharmacogenomics-based drug dosing guidelines can be found.
Organization	Description	Ref.
CPIC	CPIC was launched in 2009. It is a collaboration between the PharmGKB group and PGRN. It develops guidelines to help clinicians use genetic test results in optimization drug therapy. The guidelines are peer reviewed and published as open access in the Journal of Clinical Pharmacology and Therapeutics. CPIC uses the three-tiered rating system in which ratings of: A, strong; B, moderate; and C, optional, are applied based on the evidence reviewed. The published articles also tabulate the variable PGx tests available in the market	[113]
Table of pharmacogenomic biomarkers in US FDA-approved drug labels	This table "lists FDA-approved drugs with PGx information in their labels. Some, but not all, of the labels include specific actions to be taken based on genetic information. Relevant sections of the label with such information are noted."	[102]
EGAPP	This independent, multidisciplinary panel was established in 2005. It supports "the development of a systematic process for assessing the available evidence regarding the validity and utility of rapidly emerging genetic tests for clinical practice. The panel provides guidance on appropriate use of genetic tests in specific clinical scenarios;" hence the focus is not on PGx. Practice guidelines include genetic testing for breast and colorectal cancer. The guidelines are peer reviewed and published as open access in Genetics in Medicine	[115]
DPWG	"Established in 2005 by the Royal Dutch Pharmacist's Association. It is multidisciplinary and includes clinical pharmacists, physicians, clinical pharmacologists, clinical chemists, epidemiologists and toxicologists." It develops PGx-based therapeutic (dose) recommendations. It also aims at assisting "drug prescribers and pharmacists by integrating the recommendations into computerized systems for drug prescription and [automating] medication surveillance."	[114]

CPIC: Clinical Pharmacogenetics Implementation Consortium; DPWG: The Dutch Pharmacogenomics Working Group; EGAPP: Evaluation of Genomic Applications in Practice and Prevention; PGRN: Pharmacogenomics Research Network; PGx: Pharmacogenomics; PharmGKB: Pharmacogenomics Knowledge Base.

Table 4. Comparison of available guidelines for four commonly used drugs in primary care.
	CPIC	EGAPP	US FDA-approved drug labels	DPWG
Warfarin with CYP2C9 and VKORC1
Guidelines	Yes	No	Yes	No
Recommendation	Level A dosing recommendations	NA	Dosing based on genotype should be 'considered'	NA
Genotype-specific treatment options	It is advised to use PGx-based dosing algorithms such as the algorithms available on WarfarinDosing.org^[123] or the dosing algorithm published by the International Warfarin Pharmacogenetics Consortium. In case of no access to the algorithms, CPIC dosing guidelines are suggested	NA	Daily warfarin dosing recommendations based on genotype are tabulated	NA
Clopidogrel with CYP2C19
Guidelines	Yes	No	Yes	Yes
Recommendation	Level A dosing recommendations in ACS/PCI patients for 1/1 and 2/2. Recommendation for 1/2 is level B. No dosing recommendation for 3 and 17	NA	Dosing based on genotype should be 'considered'	Dosing recommendations for 1, 2, 3 and 17
Genotype-specific treatment options	Use prasugrel or other alternative therapy in case of *2 allele carriers	NA	"Consider alternative treatment or treatment strategies in patients identified as PM." PMs being carriers of two loss of function alleles, mainly: 2, 3, 4, 5, 6, 7 and *8	Consider an alternative drug for PM and IM phenotypes
Codeine with CYP2D6
Guidelines	Yes	No	PGx information is mentioned in the label, but there are no treatments or dosing guidelines	Yes
Recommendation	Level A recommendation for UM, EM and PM. Level B recommendation for IM	NA	No	Recommendations for PM, IM and UM
Genotype-specific treatment options	Recommend alternative drug for analgesia for patients carrying PM and UM alleles. Dosing guidelines are suggested for EM and IM	NA	"When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and inform their patients about these risks and the signs of morphine overdose." Emphasis is on nursing mothers	Recommend alternative drug for analgesia for patients carrying PM, IM and UM alleles
Selective serotonin reuptake inhibitors with CYP2D6
Guidelines	Underway	Yes	PGx information is mentioned in the label, but there are no treatments or dosing guidelines	No
Recommendation	NA	"Insufficient evidence to recommend for or against use, but use discouraged pending further research"	Precautions about potential drug interactions	NA
Genotype-specific treatment options	NA	No	No	NA

CPIC: Clinical Pharmacogenetics Implementation Consortium; DPWG: The Dutch Pharmacogenomics Working Group; EGAPP: Evaluation of Genomic Applications in Practice and Prevention; EM: Extensive metabolizer; IM: Intermediate metabolizer; NA: Not available; PGx: Pharmacogenomics; PM: Poor metabolizer; UM: Ultra metabolizer.

Table 5. Additional resources that provide useful pharmacogenomic information to healthcare practitioners.
Resource	Description	Ref.
PharmGKB	PharmGKB collects, encodes and disseminates "knowledge about the impact of human genetic variations on drug" response. It also incorporates PGx-based guidelines from CPIC and DPWG and the FDA drug label information when available	[124]
Human Genome Project Information	Provides information on the human genome project and its implications on medicine, education, ethics and research, as well as general information about PGx	[125]
US FDA	The Genomics Group, in the FDA's office of clinical pharmacology, works to advance the application of genomics in the discovery, development, regulation and use of medications. It builds and updates the PGx biomarkers in drug labels	[126]
HIV Pharmacogenomics Database	This is of particular interest for the clinical management of HIV. PGx information relevant to HIV management is available	[127]
PMC	"PMC represents a broad spectrum of more than 200 academic, industry, patient, provider and payer communities. The goal is to advance the understanding and adoption of personalized medicine concepts and products for the benefit of patients"	[128]
US NIH PGRN	This is a research group whose mission is to implement studies in basic and clinical science to solve PGx problems	[129]
The Biomarkers Consortium	This is a "public–private biomedical research partnership managed by the Foundation for the NIH that endeavors to discover, develop and qualify biomarkers to support new drug development, preventive medicine and medical diagnostics"	[130]
AACC	This is an international scientific/medical society of clinical laboratory professionals, physicians, research scientists and other individuals involved with clinical chemistry and related disciplines. It has a resource center that covers PGx information on technologies, procures, interpretation of the test result and application of those results. The site has an A–Z guide to PGx	[131]
AMA	The AMA includes resources and information on several topics such as the human genome, genetic testing and PGx	[132]
American College of Clinical Pharmacy (ACCP)	This is "a professional and scientific society that provides leadership, education, advocacy and resources enabling clinical pharmacists to achieve excellence in practice and research. They have academic books on PGx"	[133]
Pharmacogenomics ^†	This journal presents, reviews and reports by the researchers and decision-makers closely involved in this rapidly developing area	[135]
The Pharmacogenomics Journal ^†	This journal publishes "original research on basic PGx research and its clinical applications"	[134]
Pharmacogenomics Reporter ^†	This is a new weekly publication for research and technology professionals working with PGx and molecular diagnostics. This is part of the GenomeWeb Intelligence Network	[136]

^†There are various other PGx journals in addition to the ones listed in this table.
AACC: American Association for Clinical Chemistry; ACCP: American College of Clinical Pharmacy; AMA: The American Medical Association; CPIC: Clinical Pharmacogenetics Implementation Consortium; DPWG: The Dutch Pharmacogenomics Working Group; EGAPP: Evaluation of Genomic Applications in Practice and Prevention; PharmGKB: Pharmacogenomics Knowledge Base; PGRN: Pharmacogenomics Research Network; PGx: Pharmacogenomics; PMC: Personalized Medical Coalition.

Box 1. Questions that are posed by primary-care practitioners when considering pharmacogenomic testing.
Utility issues Is it mandatory that I order or refer the patient for the test? Are there simple and specific guidelines that I can refer to? What is the role of the test? Dosing adjustment versus decision to prescribe. Has there been proof of benefit to the patient tested? Should family members be tested as well? Will the resulting information include genetic data or clinical recommendations? What is the cost of the test? Is it reimbursed by third-party payers? Is the test specific for this drug only? Do the practice guidelines differ from one country to another? Clinical implementation issues Should I know everything about the test, or just enough for me to refer? Are there clinical geneticists, genetic counselors, or clinical pharmacologists who can help me? Who takes action after the tests results are out: me or a specialist? How much consultation time is needed for that test and will it be reimbursed? Which laboratories offer this test? Are the laboratories Clinical Laboratory Improvement Amendments certified? What type of biological specimen is needed? What is the turnaround time of the result? Does it matter what method the laboratory is using? What is the format of the order of the test: gene or drug? Ethical, legal and social issues Is there an association of the test results with any disease susceptibility? How to ascertain confidentiality of the results? Is there a risk for discrimination in insurability and employment?