This document discusses the use of pharmacogenomics for personalized medicine. It defines key terms like pharmacogenomics and pharmacogenetics. It describes how genetic variations can be identified and linked to differences in drug response and phenotypes. Specific examples are given of actionable genotypes for warfarin and codeine metabolism. Challenges and opportunities for further research in implementing pharmacogenomics in clinical practice are also outlined.

1. Pharmacogenomics as a tool for
personalized medicine
Nur Aizati Athirah Daud
PharmCareResearch Group
Disciplineof Clinical Pharmacy
School of Pharmaceutical Sciences
Universiti SainsMalaysia
aizati@usm.my

2. ◎Personalized Therapy
◎Definitions
◎Genetic variations/polymorphisms
◎Bridging genotype &phenotypes
◎Actionable genotypes
◎How far are we?
◎Challenges
◎Research opportunities
Outline

3. Moving from "One Drug Fits All" to Personalized Therapy

4. Genomics
Genomic medicine
Pharmacogenetics
Pharmacogenomics
Genetic variations
Polymorphisms
Genotypes

5. “
#genomics: thestudyof thecompleteset of geneticinformation
present in a cell, an organism, or species
#genomicmedicine: an emerging medical disciplinethat involves
using genomicinformation about an individual aspart of their
clinical care(e.g., for diagnosticor therapeuticdecision-making) and
thehealth outcomesand policyimplicationsof that clinical use(NIH)
#pharmacogenomics: thebranch of scienceconcerned with the
identification of thegeneticattributesof an individual that
lead tovariableresponsestodrugs(Malholtra, A)
#pharmacogenetics: thestudyof variationsof DNAand RNA
characteristicsasrelated todrug response(U.S. FDA, 2010b)

7. Genetic variations/polym orphism s

8. ◎Detected in >1%of a given population
◎SNP occur every 100-300 bases along the 3-
billion-base human genome  10-30 millions SNPs
◎Levels of functionality (nonfunctional, functional
in vitro, fuctional in vivo, clinically functional)
◎Identified with rs numbers
(e.g ABCB1rs1045642; 3435C>T,
CYP2D6*2)
Homozygous wild type/ Heterozygous /
Homozygous variant  Genotype
Single nucleotide polymorphism (SNPs)

9. https://www.ncbi.nlm.nih.gov/projects/SNP/

10. http://www.ensembl.org/index.html

11. http://www.ensembl.org/index.html

13. ◎Two functional components that link pharmacology to genetics:
○ Pharmacokinetics
○ Pharmacodynamics
Bridging genotypes & phenotypes

14. ◎CYP2D6, CYP2C9, CYP2C19 enzymes
are highly polymorphic
◎account for ~40% of hepatic phase I
metabolism
Woo &Robinson. An introduction to Pharmacogenomics. In Pharmacotherapeutics for
Advance Practice Nurse Prescribers 2016, 4th ed., U.S.

15. Classification of phenotypes
Caudleet.al. 2016. Genet. Med., January:1-9

16. Belle &Singh, 2008. American Family Physician, 77(11), 1553–1560.

17. Actionable genotypes
◎CYP2C9genotypes & warfarin
○CYP2C9*2 &*3reduced metabolism of S-warfarin
○VKORC1(3673G>A)  increase sensitivity to warfarin
○CYP2C9&VKORC1polymorphisms account for ~40% of the variability in warfarin
therapy (+age &BMI=~50%)
Plos Genet 2009;5(3):e1000433
NEngl J Med 2011;364:1144-53
Pharmacogenomics 2010;11:493-6

18. Risk of hospitalization
among patients who
underwent VKORC1and
CYP2C9genotyping, 6
months after the initiation
of warfarin therapy.
J Am Coll Cardiol 2010;55:2804-12

19. ◎CYP2D6genotype & codeine
○ fatal respiratory depression in UMmotherson codeine
○UM excessive codeine activation to morphine
○Risk of respiratory depression in breastfed infants
Actionable genotypes

20. ◎SLCO1B1 genotype & simvastatin
◎rs4149056(521T>C) reduceshepatic uptakeof statins
◎Increased therisk of myopathy (OR4.5, 95%CI 2.6-7.7)
Actionable genotypes
Link et. al., 2008. NEngJ Med. 359;8:789-799
Estimated cumulative risk
of myopathy associated
with taking80mgof
simvastatin daily, according
to SLCO1B1rs4149056
genotype.

21. How far are we?
Add picture
DNApassport by ErasmusMCRotterdam, NL
◎Up until 2015, ~15% of drugs licensed by the
European Medicines Agency (EMA) &>130 drugs
registered by the US FDAcontain pharmacogenetic
data in the product information.
◎Amplichip CYP450 – first approved
pharmacogenetic test by the FDA

23. Challenges in implementation of pharmacogenomics
◎Most pharmagenetic studieshavebeen relatively small and the
populationsstudied arenot alwayswell characterized.
◎Interpretation of pharmacogenetic data  develop clinical
algorithms to aid physicians in decision making &to establish
clinical utility
◎Major effort to educate healthcare professionals
◎Genetics is only part of the puzzle : Other parameters of drug
response i.e. environmental factors, drug interactions, medication
adherence
◎Ethical, social &legal issues : confidentiality, storage, and
accessibility of pharmacogenetic information

24. Research opportunities
◎Genetic association studies
○Case-control study
○Cohort study
○Family-based design (i.e. case-parent triad)
◎Genome-wideassociation studies(GWAS)
◎Gene-environment interaction studies(GxE)
○Case-control
○Caseonly design

26. Factors influencing fetal exposure to SRIs, divided into factors in the
maternal circulation, placenta layers and foetal circulation

28. Target drugs?
○high inter-individual variability
○narrow therapeutic index
○problemsin monitoring ADRor treatment response
○few alternativetherapeutic options

29. Thank you for
your attention