WEEK 5: PHARMACOGENOMICS

• Pharmacogenomics


  The study of how an individual's genetic inheritance affects the body's response to drugs

  
  

  How all the genes(genome) effect drug response

  
• Personalized medicine/ Precision medicine


  A medical model that separates people into different groups —with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted response or risk of disease

  
• Pharmacogenetics


  The study of the variations in a targeted gene, or group of functionally related genes for variability in drug response

  
  

  Variations in one single genes effect drug response

  
• Pharmacogenomics


  The use of genetic information to guide the choice of drug and dose on an individual basis

  
• One size fits all

  
  

  The same dose of a given drug in some patients causes very different plasma levels and different therapeutic response

  
  

  Patients respond differently to given therapeutic agent even with the same illness
• Factors affecting drug responses


  1. Physiology: Age/Gender/Pregnancy/Comorbidity/Organ dysfunction
  2. Environment: Chemical exposure/ Infection/ Circadian rhythm/ Medication
  3. Lifestyle: Diet & nutrition/ Supplement & herbs/ Smoking/ Alcohol intake/ Exercise & stress
  4. Genomic variations: Drug transporter/ Drug metabolizing enzyme/ HLA alleles/ Drug targets
• Polymorphism


  A genetic variation in the DNA sequence that is present at an allele frequency of 1% or more in a population
• Major types of sequence variations


  1. Single nucleotide polymorphisms (SNPs): >1%

  • One nucleotide base pair replaces another
  • Increase in translated amino acid lead to increase protein function

  2. Insertion/deletions (Indels): <1%

  • Nucleotide sequence is deleted or added
  • Deleted: no protein expression
  • Added: increase protein expression level

  3. Tandem repeats

  • Nucleotide sequence repeat in tandem
  • Increase protein expression level

  4. Copy number variations (CNV)

  • Abnormal number of copies in gene
  • Increase in way of duration, intensity of the effect, toxicity, PKPD

  
• Polymorphisms can affect how drugs are metabolized, absorbed, or excreted in the body
• Genetic polymorphisms that can affect drug response


  • Drug transporters (OATP, P-glycoprotein)
  • Drug metabolizing enzymes (Phase I, Phase II)
  • Drug targets (target receptor sites)
  • Human leukocyte antigen (HLA) : induced hypersensitivity
• Drug transporter (OATP1B1) polymorphism

  Linked to increased risk of rhabdomyolysis with simvastatin
• Drug metabolizing enzyme (Cytochrome P450 isoenzymes) polymorphism

  1. > 2 functional allele/allele with increased activity

  • ultrarapid- high metabolic activity

  2. 2 normal (wild type) allele

  • extensive- normal capacity

  3. 1 functional & 1 defective allele / 2 functional allele

  • intermediate- reduced capacity

  4. 2 defective allele

  • poor- no functional enzyme
• CYP enzymes


  Two copies of each gene encode for a CYP enzyme, each copy is referred to as an allele

  
  

  • 1A2
  • 2A6 / 2C9/ 2C19 / 2D6
  • 3A4 / 3A5
• Mutant alleles of phase I & II enzymes can have absent, reduced, increased or normal activity
• Clopidogrel


  Prodrug, metabolized by CYP2C19
• Genetic variation in CYP2C19 affects the metabolism and efficacy of clopidogrel (prevents platelets from clumping together)

  
  

  1. Poor metabolizer

  • reduced function => lower level of active metabolite
  • reduced platelet inhibition=> increased cardiovascular risk

  2. Intermediate metabolizer

  • higher on-treatment residual platelet activity
  • may not respond well to drug

  3. Extensive metabolizer

  • better therapeutic effect
• Trastuzumab=> for pts showing overexpression of HER 2


  Monoclonal antibody that targets human epidermal growth factor 2 (HER2) to inhibit proliferation and induce tumour cell death in metastatic breast cancer
• Warfarin


  Inhibits Vitamin K epoxide reductase complex subunit 1 (VKORC1)
• VKORC1-1639G>A polymorphism


  Results in reduced expression of VKORC1 in the liver, leading to bleeding disorders (warfarin resistance)
• CYP2C9*2 polymorphism


  Encodes an amino acid change (Arg144Cys), lowered substrate affinity (30-40% reduction in S-warfarin metabolites)
• CYP2C9*3 polymorphism


  Encodes an amino acid change (Ile459Leu), lowered substrate affinity (80-90% reduction in S-warfarin metabolites)
• CYP2C9*2 and *3 alleles are more common in European populations
• Hypersensitivity reactions to various drugs can range from mild rashes to severe skin toxicities like liver injury, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome (SJS)
• Human Leukocyte Antigens (HLA)


  Part of the major histocompatibility complex (MHC) gene family, HLA-B, HLA-DQ, and HLA-DR polymorphisms have been associated with many drug-induced hypersensitivity reactions
• HLA-B*15:02 allele


  Significant marker for carbamazepine-induced steven johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), occurs 10 to 50 times more commonly in Asian patients
• Other drugs that share the HLA-B*15:02 risk include phenytoin, lamotrigine, and oxycarbazepine
• Genetic polymorphisms in drug metabolizing enzymes, drug-drug interactions, and patient-specific factors can all contribute to adverse drug reactions
• Pharmacogenomics


  Aims to maximize drug efficacy, minimize drug toxicity and ADRs, avoid drug use by hypersensitive individuals, predict patient response, and aid in new drug development
• Pharmacogenomic biomarkers can be used to guide treatment response and predict ADR incidence

  
• Clinical outcomes of one size fits all

  • Drug toxic but beneficial
  • Drug toxic and not beneficial
  • Drug not toxic and not beneficial
  • Drug not toxic but beneficial
• Polymorphism of codeine

  1. CYP3A4: codeine -> norcodeine = no analgesic effect

  2. CYP2D6: codeine -> morphine = analgesic effect

  • poor metaboliser: less cyp2d6 activity soo less analgesic effect
  • ultra-rapid metaboliser: rapidly metabolise codeine lead to morphine overdose even with normal dose
• Types of metaboliser

  1. Poor (PM)= 2 nonfunctional allele-> little/no drug metabolism
  2. Intermediate (IM)= 1 functional+1 nonfunctional-> decreased drug metabolism
  3. Extensive (EM)= 2 functional allele-> normal drug metabolism
  4. Ultra-rapid (UM)= duplication of functional allele-> increase drug metabolism rate
• Categorised pts genotype based on predicted phenotype

  • Moderate cases: extensive and intermediate metaboliser
  • Extreme cases: ultra-rapid and poor metaboliser
• Pharmacogenetic trait mainly

  • Monogenic(single gene)
  • Polygenic(several gene, effect may be additive or interactive)
  • Multifactorial(genetic and environment contribution)
• Distribution of genotype and phenotype in population

  • Genotype: RT-PCR / RNA sequence
  • Phenotype:

  1. multimodial distribution: determination by single gene having polymorphic variants
  2. unimodial distribution: polygenic multifactorial inheritance/ monogenic inheritance but no polymorphism