Pharmacogenetics is the study of influences of a gene on therapeutic and adverse effects of drugs. Pharmacogenetics plays an important role in drug development and drug safety.

1. Pharmacogenetics
Dr. P.Naina Mohamed PhD
Pharmacologist

2. Introduction
 Pharmacogenetics is the study of influences of a gene on therapeutic and
adverse effects of drugs.
 Pharmacogenetics is also defined as the study of inherited variation in drug-
metabolizing enzymes and drug responses.
Pharmacogenetics
Pharmakon - Drug
Genetikos –
Generative (Origin)

3.  Primaquine induced hemolysis in patients with G6PD (Glucose-
6-Phosphate Dehydrogenase ) deficiency, was the first
pharmacogenetic discovery.
 The term Pharmacogenetics was coined by Vogel in 1959.
 Currently, there are over 120 drugs including voriconazole,
warfarin, carbamazepine, atomoxetine, azathioprine, irinotecan,
trastuzumab, and cetuximab whose labeling includes
pharmacogenetic discoveries.
 The Food and Drug Administration (FDA) published a guidance
document to facilitate the use of pharmacogenomic discoveries
in drug development.
http://www.ajhp.org/content/66/7/625.abstract
Introduction

4.  The pharmacokinetics of a drug can be altered by sequence
variations in drug-disposition genes.
 The pharmacodynamics of a drug can be changed by sequence
variations in drug-target genes.
http://www.ajhp.org/content/66/7/625.abstract
Divisions of Pharmacogenetics
Pharmacogenetics
Drug-disposition
Pharmacogenetics
Drug-target
Pharmacogenetics

5.  A drug’s disposition includes its absorption, metabolism, distribution, and
excretion (ADME).
 The plasma concentrations of the parent drug or its active metabolites may be
affected by a genetic polymorphism altering the function of a protein that is
involved in the disposition of a drug.
 For example, if a genetic polymorphism leads to lower activity of a metabolizing
enzyme, the plasma concentrations of the parent drug may increase and plasma
concentrations of metabolites may decrease. If only the parent drug exhibits
pharmacologic activity, the genetic polymorphism will potentiate the drug
response, including adverse drug reactions. If only the metabolites have
pharmacologic activity, then the genetic polymorphism may reduce the drug
response.
 Examples:
 Warfarin and CYP2C9 polymorphisms
 Tamoxifen and CYP2D6 polymorphisms
 Thiopurine drugs and Thiopurine S-methyltransferase (TPMT)
polymorphisms
Drug-disposition Pharmacogenetics

6.  CYP2C9*2 allele results in a 30-40% reduction in
enzymatic activity for S-warfarin metabolism.
 While CYP2C9*3 allele causes an almost complete loss
of S-warfarin metabolism.
 The patients carrying CYP2C9*2, CYP2C9*3 or both of
these two alleles would have higher serum
concentrations of S-warfarin at a given dosage.
 A study in Caucasians found that patients carrying
either CYP2C9*2 or CYP2C9*3 required significantly
lower daily dosages of warfarin to maintain a
therapeutic INR compared with patients carrying
CYP2C9*1.
Warfarin and CYP2C9 Polymorphisms

7.  Tamoxifen is commonly used for breast cancer treatment.
 Endoxifen, a metabolite of tamoxifen, is 100 times more potent than the parent
drug as a selective estrogen receptor modulator and exhibits about 7 times
higher plasma concentrations than the other active metabolites at steady state.
 CYP2D6 is involved in generating endoxifen from tamoxifen.
 CYP2D6 genotype and phenotype have been associated with variability in plasma
concentrations of endoxifen among individuals.
 The CYP2D6 phenotype traditionally classified as
 Ultraextensive metabolizer (CYP2D6*1/*1XN (gene duplication))
 Extensive metabolizer (CYP2D6*1/*1 )
 Intermediate metabolizer (CYP2D6*3/*17) or
 Poor metabolizer (CYP2D6*3/*3)
 Extensive or ultraextensive metabolizers would have significantly higher serum
concentrations of endoxifen compared with intermediate and poor
metabolizers.
Tamoxifen and CYP2D6
Polymorphisms

8.  Thiopurine S-Methyltransferase (TPMT) metabolizes
thiopurine drugs such as mercaptopurine and
azathioprine.
 Reduced TPMT activity is associated with a higher
frequency of mercaptopurine-associated adverse
events, such as neutropenia.
 Patients who do not carry TPMT*1, have extremely
low TPMT enzyme activity and almost always develop
neutropenia compared with patients with TPMT*1/*1.
 FDA has recommended that clinicians consider a
reduction in the dosage of a thiopurine in patients
carrying a nonfunctional TPMT allele.
Thiopurines and Thiopurine S-
Methyltransferase (TPMT) polymorphisms

9.  Pharmacologic effects of drugs are exerted by
modulating activities of enzymes or receptors.
 Genetic polymorphisms of drug-target enzyme or
receptor may alter the drug response.
 Fewer genetic polymorphisms in pharmacodynamic
genes have been recognized by FDA, including…
Vitamin K epoxide reductase complex subunit 1 gene
polymorphisms (VKORC1) and warfarin response
ß1-adrenergic receptor gene polymorphisms (ADRB1)
and ß-blocker response
Drug-target Pharmacogenetics

10.  VKORC1 encodes vitamin K epoxide reductase, which is inhibited
by warfarin.
 This inhibition interferes with carboxylation of vitamin K-
dependent coagulation factors II, VII, IX, and X and
anticoagulation proteins C and S.
 Two haplotypes (A and B) formed by five noncoding VKORC1
SNPs in strong linkage disequilibrium.
 The A haplotype has been shown to be associated with lower
levels of VKORC1 mRNA expression compared with B haplotype.
 Patients with A haplotype may produce smaller amounts of
VKORC1 (the warfarin target protein) than do patients with B
haplotype.
 This finding is true in Asian patients who require smaller warfarin
doses to maintain a therapeutic INR than other races since the
majority of Asians carry VKORC1 haplotype A.
VKORC1 and warfarin response

11.  Ser49Gly and Arg389Gly are two common SNPs in ADRB1.
 It is hypothesized that hypertensive patients carrying
Ser49 or Arg389 would have greater reduction in blood
pressure with ß-blocker therapy.
 Several studies have found that hypertensive patients with
Ser49Arg389/Ser49Arg389 haplotype had the greatest
reduction in blood pressure with oral metoprolol.
 Since the frequency of the Arg389 allele in ADRB1 is higher
in Caucasians (73%) than in African Americans (58%),
Caucasians are more likely to have a better blood pressure
response to a ß-blocker than do African Americans.
ADRB1 and ß-blocker response

12.  Both approaches can be used for gene-disease and
gene-drug response association studies.
http://www.ajhp.org/content/66/7/625.abstract
Pharmacogenetic Studies
Pharmacogenetic
Studies
Candidate-gene studies
Genome-wide
association study
(GWAS)

13.  In patients who have a better (or worse) drug response, the candidate-
gene approach tests how frequent an allele or a set of alleles.
 Genes are selected based on their known physiological or
pharmacologic effect on disease or drug response.
 CYP2C9*2 and CYP2C9*3 polymorphisms had previously been shown to
change the function of the CYP2C9 enzyme and were chosen to study
the association with warfarin requirements.
 The discovery of the association of VKORC1 haplotypes with warfarin
dosage requirements shows how the candidate-gene approach is used.
 The candidate-gene approach is a useful tool to study a genetic
association with drug response if there is a plausible link between the
gene and the drug response.
 The candidate-gene approach is less expensive and requires a smaller
sample size than GWAS.
 A major disadvantage of the candidate-gene approach is that it requires
prior knowledge of the function of the gene regarding the drug
response.
Candidate-Gene Studies

14.  The role of common genetic variations in disease or drug
response surveyed by Genome-Wide Association Study (GWAS).
 GWAS done by genotyping large sets of SNPs across the
genome.
 Most GWASs have been conducted as a case-control, cohort, or
family study.
 The goal is to determine whether a particular allele or a set of
alleles is more common in patients with a certain disease or a
better (worse) drug response.
 GWAS is a great tool to discover new functions of a gene or to
identify a new genetic biomarker used to evaluate drug
response.
 GWASs can be used to identify new biomarkers that could
explain the underlying mechanisms of adverse drug reactions.
 GWAS helps to understand the complex disease development
and identify the factors that affect variable drug responses.
Genome-Wide Association Study
(GWAS)

15.  Pharmacogenetics has a threefold role in the
pharmaceutical industry including…
Studying drug metabolism and
pharmacological effects
Predicting genetically determined adverse
reactions (ADRs)
Drug discovery and development and as an aid
to planning clinical trials
Role of Pharmacogenetics in
Pharmaceutical Industry

16.  Pharmacists may play a key role in applying pharmacogenetic
discoveries to patient care.
 Pharmacists can take a lead in application of pharmacogenetics in
clinical practice, since they are experts in pharmacokinetics and
pharmacodynamics.
 Some experts have suggested that pharmacists need access to
patients' genetic information in order to provide individualized
pharmaceutical care before they fill prescriptions.
 Pharmacists’ responsibilities for pharmacogenomics include…
 Promoting the optimal use and timing of pharmacogenomic
tests
 Interpreting clinical pharmacogenomic test results
 Educating other pharmacists, fellow health care professionals,
patients, and the public about the field of pharmacogenomics.
http://www.ashp.org/DocLibrary/Policy/HOD/StPharmacogenomicsPre
press.aspx
Roles of Pharmacists

17.  The drug response is probably affected by multiple
genes.
 Drug response might be predicted from a certain
pattern of polymorphisms rather than only a single
polymorphism.
 Holding sensitive information on someone’s genetic
make up raises questions of privacy and security and
ethical dilemmas in disease prognosis and treatment
choices.
Limitations of Pharmacogenetics

18. •Focused on Patient variability
•One drug in different patients with inherited
gene variants
•Predicts drug toxicity
•Useful in Patient/disease-specific healthcare
Pharmacogenetics
•Focused on drug variability
•Many drugs and one genome
•Predicts drug efficacy
•Useful in Drug discovery and development or
drug selection
Pharmacogenomics
Pharmacogenetics Vs
Pharmacogenomics

19.  Pharmacogenetics plays an important role in drug development and drug safety.
 Pharmacogenetics focuses on the effect of a single gene on drug response.
 Pharmacogenomics deals with the effects of multiple genes on drug response.
 Pharmacogenetic studies have provided strong evidence for the genetic basis of
drug response and tolerability.
 The translation of pharmacogenetic research into clinical practice is time
consuming, labour intensive and expensive.
 In future all pharmacists, not just those involved in a clinical or research setting,
will probably need to understand pharmacogenetic information for better drug
selection.
 ASHP believes that pharmacists have a responsibility to take a prominent role in
the clinical application of pharmacogenomics.
 Health-care providers will increasingly need to take pharmacogenetics into
consideration when prescribing medications.
 Each patient’s history, physical condition, gender, and ethnicity must be
considered when prescribing drugs.
Conclusion

20.  Pharmacogenetics, 2e
Wendell W Weber
 Pharmacogenetics and Individualized Therapy
Anke-Hilse Maitland-van der Zee, Ann K. Daly
 New Research on Pharmacogenetics
Linda P. Barnes
 Principles of Pharmacogenetics and Pharmacogenomics
Russ B. Altman, David Flockhart, David B. Goldstein
 Pharmacogenomics and Personalized Medicine
Nadine Cohen
References

21.  http://apha.imirus.com/pdf/2008/Feb_CE_exam.pdf
 http://www.ashp.org/DocLibrary/Policy/HOD/StPharm
acogenomicsPrepress.aspx
 http://www.medscape.com/viewarticle/590270
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC188507
5/
 http://www.ashp.org/DocLibrary/Policy/HOD/StPharm
acogenomicsPrepress.aspx
References