Lec 8- Population variability

Question 1

Variability in drug response- Clinical responses to warfarin therapy

Answer 1

• We only ‘detect’ these types of events once the drug has been marketed

Question 2

Variability in drug response- Drug efficacy

Answer 2

• Most drugs can show differential drug efficacy
• 3 possible outcomes

1. Good clinical efficacy in most subjects
2. No clinical efficacy in some
3. Adverse outcomes in others

Question 3

Variability in drug response- clinical presentation

Answer 3

*

Question 4

Variability in drug response- Why does drug response vary

Answer 4

• Contains 3x10⁹ base pairs of DNA
• Between 2 people (except identical twins) the rate of genetic variation (individuality) is about 0.1%
• 0.1% of 3 billion= 3 million base pair differences
• Single Nucleotide Polymorphism

Question 5

Variability in drug response- SNP

Answer 5

• SNPs are single base pair positions in genomic DNA at which different sequence alternatives (alleles) exist wherein the least frequent allele has an abundance of 1% or greater
• A single change in DNA sequences, slight changes in protein sequence and so efficacy of enzymes

Question 6

SNPs and CYPs (CYP examples)

Answer 6

• Many clinically important examples of SNPs are related to changes in the genetic sequence of CYP450 enzymes
• 2B6= nicotine, doxorubicin
• 2C9= Warfarin, doxorubicin
• 2C19= Diazepam, PPI
• 2D6= BB, Anti-depressants, codeine
• 3A4= Erythromycin, HIV protease inhibitors

Question 7

How does an SNP enzyme typically affect the result of enzyme

Answer 7

Question 8

Variability in drug response- why is this important

Answer 8

• If we can work this out we can separate out those who will have bad PK
• We can either not given them or change there dosing regimen
• Reducing toxicity

Question 9

SNPs in CYP enzymes: definition

Types of phenotypes

Answer 9

• CYP + CYP = EM (extensive metabolizer) = Normal
• CYP + NO CYP = IM (Intermediate metaboliser = Decreased
• NO CYP + NO CYP= PM (Poor metabolizer) = None
• CYP + +CYP = UM (Ultrarapid metabolizer) = Increased

Question 10

SNP impact on metabolism

Answer 10

• Polymorphism in drug metabolising enzymes are common are typically results in
• SNP = UM
• Normal = EM
• SNP = IM
• SNP = PM

Question 11

Variability in drug response- Ethnicity

Answer 11

• Many of the reported SNPs in CYP enzymes have been identified globally in different ethnic groups
• Some CYP enzymes shows very important SNPs in specific ethnic groups
• CYP2D6-Snps are less prominent in chinese and japanese subjects than white
• CYP2c19 is more prevalent in chinese than white subjects

Question 12

SNP examples: warfarin

Answer 12

• Ranks #1 in total mentions of deaths for drugs causing adverse effects
• Ranks among top drugs associated with hospital emergency room visits for bleeding
• Overall frequency of major bleeding range 2-16% (versus 0.1% for most drugs)
• Minor bleeding event rates in randomized control trials of new anti-cogaulantshas been as high as 29% per year
• 35,000 deaths in the US due to warfarin

Question 13

SNP: warfarin

Answer 13

• Narrow range for efficacy
  
  • Variation in response pushes patiets to the extreme INR ranges
• Very large variation in doses administered achieve anti-coagulation is common
• Dosing for warfarin is often based on a dose escalating method and essential on trial and essential on trial and error

Question 14

SNP: clopidogrel

Answer 14

• Metabolised by CYP2C19
• 3 common SNPs (which reduce or increase metabolism)
• *1= normal
• 2* => slicing defect => no acitivity
• 3* => premature stop codon => No activity
• *17 => increased transcription => Ultrarapid metabolism

Question 15

Clopidogrel

Answer 15

• Clopidogrel is a prodrug and needs to be metabolised to form the active drug
• Orally absorbed
• First-pass effect intestinal metabolism
• Liver metabolism
• Works as a pro-drug so reduced active metabolite= Inc, risk for those poor metabolisers

Question 16

Clopidogrel

Answer 16

• People who have reduced functioning of their CYP2C19 liver enzymes cannot effectively convert Plavix to its active form
• As a result, Plavix may be less effective in altering platelet activity in those people
• These poor metabolisers may not receive the full benefit of plavix treatment and mey remain at risk for heart attack, stroke and CV death

Question 17

Variability in drug response: clopidogrel

Answer 17

• Prodrug: needs to be metabolised to be active
• SNPs for CYP2C19 will impact upon the active drug
• PM = less active drug = Poor clinical efficacy = Death
• UM = More active drug = Good efficacy

Question 18

Summary

Answer 18

• Describe the reasons for variability in clinical response
• Define the term pharmacogenomics
• Describe it impacts on the PK
• Use examples of PG to discuss impacts on the PK of drugs