Pharmacogene+cs and genomics
Introduc)on
- The study of the gene/c modifica/ons of variable human responses to
pharmacological agents
- We all differ in all aspect. It is very unlikely that we would react on drugs in the same
way -> we differ on all levels
- If you have a health problem -> you go to the doctor -> diagnosis -> drug
o If this doesn’t work -> back to the doctor -> change diagnosis -> change
treatment
- What we are aiming is to move to personalized medicine
o individual risk for complex diseases
§ Because of gene/c factors
o Individual reac/on to drugs
o Feasible?
§ Need for insights into individual gene/c and environmental risk factors
§ => analysis of genome is feasible
• Clear guidelines for the use and interpreta/on of risk analysis for the
clinicals
- Many drugs only response rate between 25 and 75%
o A large number of the drugs don’t help the pa/ents
- The overall incidence of adverse drug reac/ons is about 5-10%
- Adverse effects lead to 2 million people hospitalized/ year of which 100.000 die
o They get a drug which wasn’t a good drug of them
- These unan/cipated reac/ons to medica/ons are largely gene/cally determined.
➔ Pharmacogene/cs encompasses any gene/cally determined varia/on in response to
drugs
The gesta)on of a new discipline
- Osler: medicine is not really science, more art because pa/ents are so different
- Garrod: if you give a drug some pa/ents will not react and other will overreact
- 1932: biZer taste blindness for phenylthiocarbamide with racial differences
o How we feel the taste of this product is gene/c determined
- World war II: acute hemoly/c crises in 10% of American soldiers (few Caucasian)
treated with an/malarial drug (primaquine)
o Also here the background defined how the soldiers would react
o Ethnic background has an influence
- 1957: “inheritance might explain many individual differences in the efficacy of drugs
and in the occurrence of adverse drug reac/ons” Motulsky
- 1959: “Pharmacogene/cs: the Role of Gene/cs in Drug Response” Friedrich Vogel
Evidence for gene)c determinants for drug effect
- Link between ethnicity and aberrant drug responses
- Link between inheritance and aberrant drug responses
- 1957-1970: Evidence for heritability by family and twin studies
Appearances of “pharmacogene)cs” and “pharmacogenomics” in PUBMED
- In the beginning of the century almost no papers, now we have an increase
, Adminstra)on of drugs
- Give drug to pa/ents
o Plasma concentra/on will increase
o We want to reach a concentra/on that is in the therapeu/c range -> we see the
effect of the drug
§ Below threshold -> therapeu/c failure
§ Over threshold -> toxic levels -> adverse effects
Aims of pharmacogene)cs
- Improving therapeu/c efficacy
- Reducing drug toxicity
- Reducing costs
è “Personalized medicine”
Possible explana)ons for differences in drug response
- There are number of /me points where there can be differences in the reac/on
o The way the drug is given
o Absorp/on of the drug
o Transport of the drug
o Metabolizing steps are involved
o Reach the site of ac/on: there are cells that have a receptor -> varia/on in
receptor can influence how the pa/ent will react
o Excre/on of the metabolites can also be different
- An/ epilep/c drug: Metabolized in the liver -> need to be transported through the
BBB -> effect on some parts of the brain
o On all these places varia/ons can occur
- Gene/c differences in absorp/on and transport of drugs
- Gene/c differences in metabolisa/on of drugs
- Gene/c differences in drug target
o Human growth hormone
o B1 adrenerg receptor: sensi/vity for B-blocking agents
- Differen/a/on between subtypes of a disease
o Biochemical markers
§ Can indicate with what type of disease you are dealing with
o Gene/c markers
§ Cytogene/c abnormali/es in cancer/gene/c polymorphisms
Introduc)on
- The study of the gene/c modifica/ons of variable human responses to
pharmacological agents
- We all differ in all aspect. It is very unlikely that we would react on drugs in the same
way -> we differ on all levels
- If you have a health problem -> you go to the doctor -> diagnosis -> drug
o If this doesn’t work -> back to the doctor -> change diagnosis -> change
treatment
- What we are aiming is to move to personalized medicine
o individual risk for complex diseases
§ Because of gene/c factors
o Individual reac/on to drugs
o Feasible?
§ Need for insights into individual gene/c and environmental risk factors
§ => analysis of genome is feasible
• Clear guidelines for the use and interpreta/on of risk analysis for the
clinicals
- Many drugs only response rate between 25 and 75%
o A large number of the drugs don’t help the pa/ents
- The overall incidence of adverse drug reac/ons is about 5-10%
- Adverse effects lead to 2 million people hospitalized/ year of which 100.000 die
o They get a drug which wasn’t a good drug of them
- These unan/cipated reac/ons to medica/ons are largely gene/cally determined.
➔ Pharmacogene/cs encompasses any gene/cally determined varia/on in response to
drugs
The gesta)on of a new discipline
- Osler: medicine is not really science, more art because pa/ents are so different
- Garrod: if you give a drug some pa/ents will not react and other will overreact
- 1932: biZer taste blindness for phenylthiocarbamide with racial differences
o How we feel the taste of this product is gene/c determined
- World war II: acute hemoly/c crises in 10% of American soldiers (few Caucasian)
treated with an/malarial drug (primaquine)
o Also here the background defined how the soldiers would react
o Ethnic background has an influence
- 1957: “inheritance might explain many individual differences in the efficacy of drugs
and in the occurrence of adverse drug reac/ons” Motulsky
- 1959: “Pharmacogene/cs: the Role of Gene/cs in Drug Response” Friedrich Vogel
Evidence for gene)c determinants for drug effect
- Link between ethnicity and aberrant drug responses
- Link between inheritance and aberrant drug responses
- 1957-1970: Evidence for heritability by family and twin studies
Appearances of “pharmacogene)cs” and “pharmacogenomics” in PUBMED
- In the beginning of the century almost no papers, now we have an increase
, Adminstra)on of drugs
- Give drug to pa/ents
o Plasma concentra/on will increase
o We want to reach a concentra/on that is in the therapeu/c range -> we see the
effect of the drug
§ Below threshold -> therapeu/c failure
§ Over threshold -> toxic levels -> adverse effects
Aims of pharmacogene)cs
- Improving therapeu/c efficacy
- Reducing drug toxicity
- Reducing costs
è “Personalized medicine”
Possible explana)ons for differences in drug response
- There are number of /me points where there can be differences in the reac/on
o The way the drug is given
o Absorp/on of the drug
o Transport of the drug
o Metabolizing steps are involved
o Reach the site of ac/on: there are cells that have a receptor -> varia/on in
receptor can influence how the pa/ent will react
o Excre/on of the metabolites can also be different
- An/ epilep/c drug: Metabolized in the liver -> need to be transported through the
BBB -> effect on some parts of the brain
o On all these places varia/ons can occur
- Gene/c differences in absorp/on and transport of drugs
- Gene/c differences in metabolisa/on of drugs
- Gene/c differences in drug target
o Human growth hormone
o B1 adrenerg receptor: sensi/vity for B-blocking agents
- Differen/a/on between subtypes of a disease
o Biochemical markers
§ Can indicate with what type of disease you are dealing with
o Gene/c markers
§ Cytogene/c abnormali/es in cancer/gene/c polymorphisms
