pharmacogenetics

Pharmacogenetics

Shailendra ShakyaKathmandu University

Differential drug efficacy

Same symptoms,Same findings,Same disease? Same drug

Same dose

Different Effects

Different patients

At a recommended prescribed dosage—

a drug is efficacious in most.

not efficacious in others.

harmful in a few.

Lack of efficacy

Unexpected side-effects

Why does drug response vary?

Same symptoms,Same findings,Same disease? Same drug

Same dose

Different Effects

Possible Reasons: Individual variation By chance…

Different patients

EthnicityAgePregnancyGenetic factorsDiseaseDrug interactions……

Genetic Differences

A

GSNP

Why does drug response vary? Genetic variationPrimarily two types of genetic mutation events

create all forms of variations:Single base mutation which substitutes one

nucleotide for another --Single nucleotide polymorphisms (SNPs)

Insertion or deletion of one or more nucleotide(s)

--Tandem Repeat Polymorphisms --Insertion/Deletion Polymorphisms

Polymorphism: A genetic variation that is observed at a

frequency of >1% in a population

Single nucleotide polymorphisms (SNPs)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.

For example a SNP might change the DNA sequence

AAGCTTACto ATGCTTAC

SNPs are the most commonly occurring genetic differences.

Single nucleotide polymorphisms (SNPs)

SNPs are very common in the human population.

Between any two people, there is an average of one SNP every ~1250 bases.

Tandem Repeat Polymorphisms

Tandem repeats or variable number of tandem repeats (VNTR) are a very common class of polymorphism, consisting of variable length of sequence motifs that are repeated in tandem in a variable copy number.

Based on the size of the tandem repeat units:Microsatellites or Short Tandem Repeat (STR)

repeat unit: 1-6 (dinucleotide repeat: CACACACACACA)

Minisatellitesrepeat unit: 14-100

Insertion/Deletion PolymorphismsInsertion/Deletion (INDEL)

polymorphisms are quite common and widely distributed throughout the human genome.

Due to individual variation…20-40% of patients benefit from an approved

drug70-80% of drug candidates fail in clinical trialsMany approved drugs removed from the market

due to adverse drug effects

The use of DNA sequence information to measure and predict the reaction of individuals to drugs.

Personalized drugsFaster clinical trialsLess drug side effects

Pharmacogenetics

Pharmacogenetics“Study of interindividual variation in DNA sequence

related to drug absorption and disposition (Pharmacokinetics) and/or drug action (Pharmacodynamics) including polymorphic variation in genes that encode the functions of transporters, metabolizing enzymes, receptors and other proteins.”

“The study of how people respond differently to medicines due to their genetic inheritance is called pharmacogenetics.”

“Correlating heritable genetic variation to drug response”

An ultimate goal of pharmacogenetics is to understand how someone's genetic make-up determines, how well a medicine works in his or her body, as well as what side effects are likely to occur.

Pharmacogenetics VS. PharmacogenomicsPharmacogenetics: Study of variability in

drug response determined by single genes.

Pharmacogenomics: Study of variability in drug response determined by multiple genes within the genome.

The term pharmacogenetics comes from the combination of two words:

Pharmacology and Genetics

Pharmacogenetics is the study of genetic factors that influence how a drug responses.

Exogenous & Endogenous factors contribute to variation in drug response

PharmacogeneticsPharmacogenetics is the study of how genes

affect the way people respond to drug therapy. The goal of pharmacogenetics is to individualize drug therapy to a person's unique genetic makeup. The environment, diet, age, lifestyle, and state of health can influence a person's response to medicine. An understanding of an individual's genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety.

pharmacogenomicsPharmacogenomics involves study of the role

of genes and their genetic variations (DNA, RNA level) in the molecular basis of disease, and therefore, the resulting pharmacologic impact of drugs on that disease.

AIM OF PHARMACOGENETIC STUDIES

Identify and categorize the genetic factors that underlie the differences and apply this in clinical practice

Rational, individual therapy Screening for those patients who carry the

genes which place them at risk in case of certain therapies

Discovering which drugs are potentially dangerous for carriers of a given polymorphism

Establishing the frequency of pharmacogenetic phenotypes

ApplicationApplication of pharmacogenetics to pharmacokinetics

and pharmacodynamics helps the development of models that predict an individual's risk to an adverse drug event and therapeutic response.

With some drugs, pharmacogenetics allows the recognition of subgroups with different genetic makeup that results in alterations in drug receptors and the pharmacodynamic response to drugs.

Understanding the genetic and molecular differences in disease etiology and drug mechanism produce insight on how a patient will respond to a given drug.

DNA IS INFORMATIONDNA

A, T, G, C

Codon

Gene

Chromosome

Genome

ENGLISH

Abcdefg….xyz

Word

Sentence

Chapter

Book

Genetic polymorphismPolymorphisms or genetic variations with a

frequency of greater than 1% of the population, or mutations, in less than 1% of the population, in genetic sequences can affect .

Pharmacokinetic parameters now known to be influenced by genetic differences include drug bioavailability, distribution, metabolism and tissue binding.

GENETIC POLYMORPHISMSPharmacokinetic

-Transporters-Plasma protein binding

-Metabolism

Pharmacodynamic

-Receptors-Ion channels

-Enzymes-Immune molecules

Polymorphism in cytochrome isozymes is well known in drug metabolism. Genetic tests are available to screen polymorphisms for cytochrome P-450 drug-metabolizing enzymes in an individual. Prior knowledge of an individual's metabolic capability can reduce the risk of adverse drug reactions because dose regimens may be adjusted according to an individual patient's metabolic capability.

The differences in the response to a given drug can be attributed to two major factors that are under genetic influence:

Pharmacokinetic: genetically based differences in the processes influencing bioavailability

Pharmacodynamic: genetically based differences in the proteins at which the drug acts

Gene product(Gene) Drugs Responses affected

Dihydropyrimidine dehydrogenase

Fluorouracil 5-Fluorouracil neurotoxicity

N- acetyltransferase (NAT2)

Isoniazid, hydralazine, sulfonamides, amonafide,

Hypersensitivity to sulfonamides, amonafide toxicity, hydralazine-induced lupus, isoniazid neurotoxicity

Glutathione transferases(GSTM1, GSTT1, GSTP1)

Several anticancer agents

Decreased response in breast cancer, more toxicity and worse response in acute myelogenous leukemia

Thiopurine methyl-transferase (TPMT)

Mercaptopurine, thioguanine, azathioprine

Thiopurine toxicity and efficacy, risk of second cancers

EXAMPLES OF GENETIC POLYMORPHISMS INFLUENCING DRUG RESPONSE

Adverse Drug Reactions Attributed to Genetic Differences

Enzyme/Receptor

Frequency of Polymorphism

Drug Drug Effect/Side Effect

CYP2C9 14–28% (heterozygotes)

Warfarin Hemorrhage

  0.2–1% (homozygotes)

Tolbutamide Hypoglycemia

    Phenytoin Phenytoin toxicity

    Glipizide Hypoglycemia     Losartan Decreased

antihypertensive effect

CYP2D6 5–10% (poor metabolizers)

Antiarrhythmics Proarrhythmic and other toxic effects

More powerful medicines:

Safer drugs the first time:

More accurate methods of determining dosages:

Better vaccines:

POTENTIAL BENEFITS OF PHARMACOGENETIC

STUDY

Drug response Drug target Drug metabolism Drug development

PHARMACOGENETICS IN PRACTICE

The systematic identification and functional analysis of human genes is changing the study of disease processes and drug development. Pharmacogenetics enable clinicians to make reliable assessments of an individual's risk of acquiring a particular disease, be more specific in targeting drugs, and account for individual variation of therapeutic response and toxicity of drugs.

Good luck !!!