Shailendra Shakya Kathmandu University

Same symptoms, Same findings, Same disease?

Different patients

Same drug Same dose

Differential drug efficacy

Different Effects 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

Same symptoms, Same findings, Same disease?

Different patients

Same drug Same dose

Why does drug response vary?

Genetic Differences
G A

Different Effects
Ethnicity Age Pregnancy Genetic factors Disease Drug interactions

SNP

Possible Reasons: Individual variation By chance

Why does drug response vary?

Genetic variation Primarily 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

to

AAGCTTAC ATGCTTAC differences.

SNPs are the most commonly occurring genetic

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 CACACACACACA) Minisatellites repeat unit: 14-100

(dinucleotide

repeat:

Insertion/Deletion Polymorphisms Insertion/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 drug

70-80% of drug candidates fail in clinical trials

Many 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 drugs

Faster clinical trials
Less 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. Pharmacogenomics Pharmacogenetics: 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:

Exogenous & Endogenous factors contribute to variation in drug response

Pharmacogenetics
Pharmacogenetics 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.

pharmacogenomics
Pharmacogenomics 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

Application
Application 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 INFORMATION
DNA ENGLISH

A, T, G, C
Codon

Abcdefg.xyz
Word

Gene
Chromosome Genome

Sentence
Chapter Book

Genetic polymorphism
Polymorphisms 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.

 Polymorphism in cytochrome isozymes is well known

in drug metabolism. Genetic tests are available to screen polymorphisms for cytochrome P-450 drugmetabolizing 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

EXAMPLES OF GENETIC POLYMORPHISMS INFLUENCING DRUG RESPONSE

Gene product(Gene) Dihydropyrimidine dehydrogenase N- acetyltransferase (NAT2) Drugs Fluorouracil Responses affected 5-Fluorouracil neurotoxicity

Isoniazid, hydralazine, sulfonamides, amonafide, Several anticancer agents

Hypersensitivity to sulfonamides, amonafide toxicity, hydralazine-induced lupus, isoniazid neurotoxicity Decreased response in breast cancer, more toxicity and worse response in acute myelogenous leukemia Thiopurine toxicity and efficacy, risk of second cancers

Glutathione transferases (GSTM1, GSTT1, GSTP1)

Thiopurine methyltransferase (TPMT)

Mercaptopurine, thioguanine, azathioprine

Adverse Drug Reactions Attributed to Genetic Differences

Enzyme/Receptor Frequency of Polymorphism CYP2C9 1428% (heterozygotes) 0.21% (homozygotes) Drug Warfarin Tolbutamide Phenytoin Glipizide Losartan Drug Effect/Side Effect Hemorrhage Hypoglycemia Phenytoin toxicity Hypoglycemia Decreased antihypertensive effect Proarrhythmic and other toxic effects

CYP2D6

510% (poor metabolizers)

Antiarrhythmics

POTENTIAL BENEFITS OF PHARMACOGENETIC STUDY

More

powerful medicines:

Safer drugs the first time: More accurate methods of determining

dosages:
Better vaccines:

PHARMACOGENETICS IN PRACTICE
Drug response
Drug target

Drug metabolism
Drug development

 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 !!!