Clinical Pharmacogenomics Barry J. Gales, Pharm.D. Professor, College of Pharmacy Southwestern Oklahoma State University [email protected]Objectives Explain the influence that pharmacogenomics has on drug metabolism. Identify current resources for pharmacogenomics information. Discuss clinical practice issues surrounding pharmacogenomics. Review current status and future of pharmacogenomic testing.
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OSHP 4-17 (Gales)Gales)_… · Clinical Pharmacogenomics Barry J. Gales, Pharm.D. Professor, College of Pharmacy Southwestern Oklahoma State University [email protected] Objectives
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Clinical Pharmacogenomics
Barry J. Gales, Pharm.D.Professor, College of Pharmacy
Explain the influence that pharmacogenomics has on drug metabolism.
Identify current resources for pharmacogenomics information.
Discuss clinical practice issues surrounding pharmacogenomics.
Review current status and future of pharmacogenomic testing.
Question 1
What region of a gene is responsible for coding for protein production?a. Exonb. Intronc. Regulatoryd. SNPs
Question 2
Where is the best place to get drug specific pharmacogenomic recommendations?a. Wikipediab. Human Genome Projectc. American College of Medical
Geneticsd. Clinical Pharmacogenetics
Implementation Consortium
Question 3
Which of the following are challenges to the implementation of pharmacogenomics?a. Lack of data standardizationb. Lack of EHR integrationc. Cost of testingd. Data variability and discordancee. All of the above
Definitions
Pharmacogenetics – monogenetic variants affecting drug response.
Pharmacogenomics – entire spectrum of genes that interact (enzymes, transport proteins, receptors) to determine drug response.
Terms are frequently used interchangeably
Precision/Personalized Healthcare/Medicine
Human Genome Project
Commissioned by Congress in 1988
Goal – sequence entire human genome by 2005
Initiated in 1990
Completed in 2003 – 99% of gene-containing sequence with a 99.9% accuracy.
Genome Research Resources
Human genome available at National Center for Biotechnology Information website.
International HapMap Project1000 Genomes project – catalog less common
genetic variantsPharmacogenomics Research Network
(PGRN)
Human Genome Facts
3.2 billion nucleotide base pairs
Base pairs code for ~ 22,000 protein-coding genes
Only 0.1% of base pair variation makes us individuals (99.9% genetically identical)
Can now sequence 40 billion bases/hour
Human Genome Facts
Codon – 3 consecutive nucleotides
Codons code for individual amino acids or amino acid chain termination
Substantial coding redundancy – GGC, GGG & GGT all code for glycine
20 amino acids form all human proteins
Human Genome Facts
A gene is a series of codons that specify for a particular protein
Gene regionsExons – encode for final protein
production (1% of genome)Introns – intervening noncoding regionsRegulatory – control gene transcription
Human Genome Facts
Alleles – sequence of nucleic acid bases at a given gene chromosomal locus.
Each gene locus made up of 2 alleles (parents)Homozygous genotype – 2 identical allelesHeterozygous genotype – 2 different allelesPhenotype is the outward expression of the
Polymorphisms (>1% of population) –responsible for most genetic variability in metabolic function or drug responses
Single-nucleotide polymorphisms
SNPs (snips) most common genetic variationOccur ~1/300 base pairsSNPs single base pair differences between individualsProteins &/or function maybe altered
Wild type allele – original or most common Variant allele – less common or variant copy
Clinical Pharmacogenetics Implementation Consortium (CPIC)International consortium providing guidance on how to use & incorporate existing pharmacogenetic data into the EHR NOTwhether to obtain pharmacogenetic data
CPIC guidelines & additional information are at the Pharmacogenomics Knowledge Base website (www.PharmGKB.org)
Published CPIC Guidelines
Do NOT address merit/need of/for testingUtilize a standard formatFull articles available on PharmGKB.orgPharmGKB.org summarizes genotypes,
phenotypes, implications, therapeutic recommendations & strength of recommendations
NIH sponsoredLaunched in 2013Genetic data from patients, clinicians,
laboratories and researchersAuthoritative central resource that defines the
clinical relevance of genomic variantsClinVar database developed to handle data
Clinical Genome Resource (ClinGen) Goals
Centralized shareable databaseStandardize annotation, interpretation and
weighting of genomic variantsAssess the “medical action ability” of variantsStructure genomic data for EHR useEnhance genomic use in diverse populationsDevelop expert panels to interpret data
Genomic Testing Results
52,000 adults followed for 5 years – 64.8% received a drug known to be influenced by pharmacogenomics (potential issue)
91% of patients had actionable results following 5 gene preemptive testing
Clin Pharmacol Ther 2012;92:235-42.
Genomic Testing Results
78% pediatric patients with actionable results following 4 gene preemptive testing
97% US patients with actionable results following 12 pharmacogene testing
738,000,000 RXs in 2013 for the 30 most common drugs with actionable results
Am J Med Genet C Semin Med Genet 2014;166C:45-55.Annu Rev Pharmacol Toxicol 2015;55:89-106.
Genomic Testing Results
5 CYP Isoenzymes
22,225 patients tested
20,534 patients with medication lists
Mean age 60y (1-108 y)
Mean # drugs 9.1 (1-49) Am J Health-Syst Pharm 2016;73:61-7
Genomic Testing Results
7% with NO at risk phenotype33% with ONE at risk phenotype41% with TWO at risk phenotypes17% with THREE at risk phenotypes2% with FOUR at risk phenotypes6 patients had FIVE at risk phenotypes
Genomic Testing Results
69.1% with at least one DDI, DGI or DDGI
8.9% with >1 “Change” interaction36.7% with >1 “Consider Change” interaction23.5% with >1 “Monitor” interaction30.9% with >1 “No Change” needed
Testing discordance between laboratories is not uncommon
Data is in silos not large usable poolsClinical presentation may be discordant with
genetic testing resultsData on UMs & PMs most useful currentlyHow to protect genetic patient information
Clinical Practice Issues
How do we determine what are “actionable findings”?
Does the action ability of findings differ for initiation of drug therapy vs. continuation of drug therapy?
Clinical Practice Issues
Will hospitals be expected to utilize/develop pharmacogenomic driven patient specific formularies?
Will insurers be expected to consider pharmacogenomics when making drug coverage and prior authorization decisions?
Clinical Practice Issues
Exome testing – sequences only protein producing section of the DNA. This is faster cheaper and the most common type of assay.
Genome testing – sequences whole DNA profile. Slower, more expensive but potentially may provide important data from the reactive region and introns we will need.
Reactive vs. Pre-emptive GenotypingReactive – ordered when a drug is being considered, delay in reporting, limited data (2C19 for clopidogrel)
Pre-emptive – data in EHR, more complete data, continuously available, less expensive in long run, requires good decision support software; Run at birth????
Question 1
What region of a gene is responsible for coding for protein production?a. Exonb. Intronc. Regulatoryd. SNPs
Question 2
Where is the best place to get drug specific pharmacogenomic recommendations?a. Wikipediab. Human Genome Projectc. American College of Medical
Which of the following are challenges to the implementation of pharmacogenomics?a. Lack of data standardizationb. Lack of EHR integrationc. Cost of testingd. Data variability and discordancee. All of the above