Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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2 Applying Pharmacogenomics in TherapeuticsClinical Relevance................................................................................................ 16Testing Availability and Recommendations......................................................... 17Dosing: Warfarin....................................................................................................... 17Clinical Case........................................................................................................ 17Background.......................................................................................................... 17Gene/Allele of Interest and Functional Effect..................................................... 17Clinical Relevance................................................................................................ 18Testing Availability and Recommendations......................................................... 18Educational Resources.............................................................................................. 18Challenges of Pharmacogenomics and Personalized Medicine................................ 21Availability of Testing.......................................................................................... 21Small Sample Size............................................................................................... 21Knowledge and Education of Healthcare Professionals...................................... 21Summary...................................................................................................................22Study Questions........................................................................................................22Case 1...................................................................................................................22Case 2...................................................................................................................23References.................................................................................................................24KEY CONCEPTS• Advances in pharmacogenomics have demonstrated its usefulness in predictingdrug efficacy, toxicity, and dosing for various disease states.• When interpreting pharmacogenomic information, gene/allele of interest,functional effect, clinical relevance, and testing availability and recommendationsare key areas to consider.• Pharmacogenomic data contribute to omeprazole pharmacokinetic variability,trastuzumab efficacy, and warfarin dosing. In addition, abacavir,codeine, and carbamazepine toxicity can be explained in part bypharmacogenomics.• Challenges of pharmacogenomics and clinical implementation includeavailability of cost-effective, rapid-turnaround pharmacogenomic tests andknowledge and education of healthcare professionals.INTRODUCTIONPharmacogenomics is a rapidly expanding field that will have a significant impact onpatient care and the role of healthcare professionals in providing personalized care.The clinical implications of utilizing pharmacogenomic information range acrossmaximizing drug efficacy, minimizing drug toxicity, and avoiding unnecessary drugtherapy. The ability of clinicians to obtain, interpret, and utilize pharmacogenomicinformation in a timely and efficient manner will determine their ability to individualizepharmacotherapy for their patients.Pharmacogenomics also has the potential to optimize drug development. Patientpopulations can be stratified according to their pharmacogenomic profiles and subsequentlybe used to study the effectiveness of an investigational drug for specific
Concepts in Pharmacogenomics and Personalized Medicine3patient genotypes and phenotypes. Variations in a gene may impact either the pharmacokinetics(PK) or pharmacodynamics (PD) of a drug, which in turn affectsclinical outcomes. PK is the process by which a drug is absorbed, distributed, metabolized,and excreted by the body (ADME); in essence, “what the body does to thedrug?” PD is the effect of a drug on the body; in other words, “what the drug does tothe body?” These factors can potentially determine the efficacy or toxicity of a drug;for example, a polymorphism may lead to increased drug plasma concentrations,which, in turn, translates to increased drug effectiveness or adverse effects.Pharmacogenetics is defined as “the study of genetic causes of individual variationsin drug response.” 1 Pharmacogenomics is defined as “the genome-wide analysisof genetic determinants of drug efficacy and toxicity.” 2 Although the terms maybe used interchangeably, we use the term pharmacogenomics in this chapter.The purpose of this chapter is to provide an overview of the drugs whose pharmacogenomicapplications could demonstrate their place in the prediction of drugefficacy, toxicity, and dosing. We review six important drugs as they relate to eachcategory: omeprazole (efficacy), trastuzumab (efficacy), abacavir (toxicity), codeine(toxicity), carbamazepine (toxicity), and warfarin (dosing). Although these six examplesvary in levels of evidence and recommendations for testing in clinical practice,they portray the current state of clinical applications (or lack thereof) in real-worldpractice. For each drug, we present a clinical case scenario, background of the drug,gene/allele of interest and functional effect, clinical relevance and testing availability,and recommendations. At the end of this chapter, we discuss several challenges inimplementing pharmacogenomic testing in clinical practice, including availabilityof tests, generalizability of scientific evidence, and knowledge and education ofhealthcare professionals.DefinitionsA polymorphism is defined as a DNA sequence variant present in >1% of the generalpopulation. 3 If a DNA sequence variant is present in <1% of the population,it is defined as a mutation. An allele refers to two different versions, or alternatesequences, of the same gene localized at any position on a chromosome. Withina gene, variations of an individual nucleotide can be considered alleles. Allelesinclude the wild type: that is, the usual sequence, mutations, and polymorphisms ofa given gene. Since humans are diploid organisms, there are two alleles (one fromeach parent) of each gene. Each person carries a set of two alleles of each gene,and this is defined as the genotype. A phenotype is the set of characteristics or theclinical presentation of an individual, which results from the particular genotype.For example, variations in the cytochrome P450 (CYP) genes may result in thecontrasting phenotypes of ultrarapid metabolizers (UMs) and poor metabolizers(PMs) of the affected drug. A haplotype is a set of alleles at multiple, neighboringpositions that coexist on the same chromosome. These alleles may be in separatelocations within a single gene or among different genes. Neighboring alleles(located near one another) are physically tethered and usually inherited as a setthat prevents their separation during inheritance. One individual inherits two copiesof a haplotype.
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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