2. HISTORY
A
ed that ingestion of fava beans resulted in
al reaction in some individuals.
B
mics study
n phenylthiocarbamide
med that chemicals react differently
makeup of an individual
C
"pharmacogenetics" to
rences in drug response
D
uence
h integrated
enes and other
E
HGP)
F
6. -
Precisionmedicine
• Individual variations in genes
• Individual variations in environment
• Individual variations in lifestyle
• Advance pharmacogenomics –The RIGHT DOSE OF RIGHT DRUG FOR RIGHT
INDICATION FOR THE RIGHT PATIENT AT THE RIGHT TIME.
• Identify new targets for treatment and prevention
• Lay scientific foundation for precision medicine for many diseases
LONG TERM GOALS
7. pharmacogenomics
Pharmacogenomics (PGx)
Effect of gene on drug response.
Combination of 2 field - pharmacology (the science of drugs) and
genomics (the study of genes and their functions).
Necessity of Pharmacogenomics- Genes influence drug response.
Genes undergo variation in individual by:
acquired and inherited genetic variation
gene expression
single-nucleotide polymorphisms
INSERTION, DELETION, COPY NUMBER VARIATION
PK/PD
8. • A Single Nucleotide Polymorphism (SNP) are DNA sequence variation that occurs when a single
nucleotide in the genome sequence is altered.
…CTAGATACGAACTGCATC…
…CTAGATACGGACTGCATC…
Occur in at least 1% of the population and make up about 90% of all human genetic variation
SingleNucleotidePolymorphism
10. Consequences of polymorphism
Pharmacokinetic
Variations
( involving drug
metabolism )
Pharmacodynamic
Variations
(involving drug-receptor
interactions)
Phase I Phase II
Isoniazid
N Acetyl
transferase
Slow Acetylators
Fast Acetylators
Acetylation
Polymorphism of N-acetyl transferase
Acetylation of Isoniazid
Fast acetylators
hepatotoxicity
slow acetylators
peripheral neuropathy
Genetic polymorphism
Abnormal rynodine receptor on
sarcoplasmic reticulum
Excessive release of calcium
Halothane induced hyperthermia
Haemolysis due to G6PD
deficiency.
Insulin resistance due to receptor
mutations
11. Metabolism is most affected
Slow metabolism-toxic Fast metabolism- t1/2 too rapid
Cytochrome P-450 (CYP450)
• enzymes of phase I metabolism- CYP1A2, CYP2A9, CYP2C19, CYP2D6,
CYP3A4, etc.
• Involved with 80% drug metabolism
Relationship between Genetic variation and PK
• Affected by genetic variation
RelationshipbetweenGeneticvariationandPK
12. • PM: no functional allele
• IM: one reduced + one non-functional allele
• EM: one full function + one non-functional/ one full function + one reduced
function/ two full function/ two reduced function
• UM: more than two functional allele
• * indicate the allele (i.e. which genetic variation)
• In drug metabolizing enzyme, allele is composed of a number of genetic variation
(in form of haplotype)
Metabolic phenotype: determined by the drug
metabolizing enzyme activity
13. GENE PRODUCT (GENE) RESPONSES AFFECTED
CYP2C9
Anticoagulant effect of
warfarin
CYP2C19
Peptic ulcer response to
omeprazole
CYP2D6
Tardive dyskinesia from
antipsychotics, narcotic side
effects, codeine efficacy,
imipramine dose requirement,
β blocker effect
15. Stevens-Johnson Syndrome:
Severe cutaneous adverse reaction of drugs (SCAR)
Mostly drug induced
Idiosyncratic in nature
• 2004: A strong association of CBZ-induced SJS with
HLA-B in Han Chinese was first uncovered in Taiwan
SJS/TENANDAGRANULOCYTOSIS
Agranulocytosis:
Thiourea antithyroid drugs (ATDs):
Carbimazole (CMZ)/ methimazole (MMI)
Propylthiouracil (PTU)
SJS/TEN AND AGRANULOCYTOSIS
17. Age
Increased age = decreased dose
Height and Weight
taller and/or weight more = higher warfarin dose
Ethnicity
Ancestry plays an important role
Asians: may need lower doses than Caucasians
African Americans: may need higher doses.
Diet
Warfarin works by inhibiting vitamin K.
consuming large amounts of vitamin K (through
foods or supplements) = higher warfarin doses.
Other Medications, Herbs, or Supplements
Many prescription and over-the-counter medications
interact with warfarin.
Inform prescribing physician of all medications, herbs, &
supplements taking
Other Health Conditions
Some diseases affect how our bodies respond to
medications
Warfarin (Coumadin): Factors Affecting Dose/Response
The CYP2C9 and VKORC1 Genotypes
CYP2C9 gene variant VKORC1 gene variant
FACTORS
18. • Aggressive form of breast CA
• Associated with genetic variation leading to
overproduction of protein called HER2
• Tumor samples tested for high levels of HER2
• Herceptin (Trastuzumab) is indicated
HER2 + Breast Cancer: Target Therapies Affecting Tumor Growth
Herceptin (trastuzumab) is an antibody that
blocks the cell surface receptor and thereby
prevents further growth. As a result, disease
progression is slowed down.
In certain types of breast cancers, the Her-2
gene is over-expressing this cell surface
receptor, contributing to cancerous cell growth.
This is the case in approximately 30% of breast
cancers.
In a normal breast tissue cell, the Her-2 gene is
expressing cell surface receptor required for
normal cell growth
19. First diagnostic- BRAC1: Myriad genetics (1997)
Diagnostics in pharmacogenomics
• Determine the genotype of the patient in terms of two
CYPP450 enzymes: 2D6 and 2C19
• FDA approved the test on December 24, 2004. The
AmphiChip CYP450 test is the first FDA
approved pharmacogenetic test.
Amphichip
20. 1. Through the development of individual pharmacogenomic
profiles, an individual's privacy and confidentiality are at risk
3. Since the drugs are more focused, the test
groups become smaller, which can lead to rare
and more fatal Adverse Drug Reactions
4. Developing drugs beneficial to one group but
dangerous to another
ETHICAL CONCERNS
2. Certain individuals (such as Health Insurance Companies
or Employers) can obtain the profiles of others and use the
"weak points" in their genes to discriminate.
Genetic Information Nondiscrimination
Act of 2007 in hopes of protecting individuals from genetic
discrimination in terms of health insurance and
employment).
21. Many drugs that are currently available are “one size fits all,” but they don't work the
same way for everyone. It can be difficult to predict who will benefit from a medication,
who will not respond at all, and who will experience negative side effects (called adverse
drug reactions). Adverse drug reactions are a significant cause of hospitalizations and
deaths. With the knowledge gained from the Human Genome Project, researchers are
learning how inherited differences in genes affect the body’s response to medications.
These genetic differences will be used to predict whether a medication will be effective for
a particular person and to help prevent adverse drug reactions.
The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but
new approaches are under study in clinical trials. In the future, pharmacogenomics will
allow the development of tailored drugs to treat a wide range of health problems, including
cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.
CONCLUSION & DISCUSSION
22. REFERENCES
Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into
rational therapeutics. science. 1999 Oct 15;286(5439):487-91.
Evans WE, McLeod HL. Pharmacogenomics—drug disposition, drug targets, and
side effects. New England journal of medicine. 2003 Feb 6;348(6):538-49.
Thorn CF, Klein TE, Altman RB. Pharmacogenomics and bioinformatics:
PharmGKB. Pharmacogenomics. 2010 Apr;11(4):501-5.
Collins FS. 2010. The Future of Personalized Medicine. NIH Medline Plus
5(1):2–3.
Ingelman-Sundberg M, Sim SC, Gomez A,Rodriguez-Antona C. (2007). Influence of
cytochrome P450 polymorphisms on drug therapies:Pharmacogeneic,
pharmacoepigenetic, and clinical aspects. Clin Pharmacol Ther 116:496–526.