The topic of pharmacogenetics and pharmacokinetics will be explored in this presentation, with a focus on how the way drugs are metabolized can be affected by genetics, and how this information can be used to personalize drug therapy. Topics such as drug response, drug metabolism, drug-drug interactions, and adverse drug reactions will be covered. The importance of pharmacokinetic profiling and therapeutic drug monitoring in ensuring drug safety and effectiveness will also be discussed. Valuable insights into the field of pharmacology and its potential to revolutionize patient care will be provided, making this presentation of interest to healthcare professionals, researchers, and those who wish to learn more about personalized medicine. The world of pharmacogenomics and genomic medicine will be delved into. The presentation will also highlight the importance of pharmacodynamics and pharmacokinetics in drug development and clinical pharmacology. By the end of this presentation, you will have a better understanding of the underlying principles of pharmacogenetics and pharmacokinetics and how they can be applied to optimize drug therapy for individual patients. This knowledge is essential for anyone involved in healthcare and drug development, as it has the potential to improve treatment outcomes and reduce adverse drug reactions.

1. PHARMACOGENETICS
AND
PHARMACOKINETIC
CONSIDERATIONS
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2. • Inter-individual variability in drug response be it efficacy or safety, is common and likely
to become an increasing problem globally.
• Reasons for this inter-individual variability include genomic factors, an area of study
called Pharmacogenomics.
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• Pharmacogenetics involves the search for genetic
variations that lead to interindividual differences in
drug response.
• The term pharmacogenetics often is used
interchangeably with the term pharmacogenomics.
• However, pharmacogenetics generally refers to
monogenetic variants that affect drug response,
whereas pharmacogenomics refers to the entire
spectrum of genes that interact to determine drug
efficacy and safety.

3. • The goals of pharmacogenetics are to optimize drug therapy and limit drug toxicity
based on an individual's genetic profile.
• Thus, pharmacogenetics aims to use genetic information to choose a drug,
drug dose, and
treatment duration
• That will have the greatest likelihood for achieving therapeutic outcomes with the least
potential for harm in a given patient.
• Genotype-guided therapy is already a reality for some diseases, such as cancer and
cystic fibrosis, where novel drugs have been developed to target specific mutations.
EXAMPLES-Trastuzumab (HER2)
Dasatanib (BCR-ABL)
Sunitinib (CSFIR + more)
3
Application of genotype-guided cancer therapy in solid tumours, JAI N Patel, Pharmacogenomics 2014 15:1, 79-93

4. HISTORY
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2000- Pharmacogenetics Research Network & Pharm GKB (database)
1977-1988 – Increasing number of genetic varients and their corrensponding
enzymatic functions were reported.
Werner kalow, German clinical pharmacologist created framework for
pharmacogenetics in his book pharmacogenetics: heredity and drug
response.
1959- Friedrich vogel, German genecist coined term ‘Pharmacogenetics’
1957- Arno Motulsky, a pioneer of medical genetics, published paper titled,
“Drug reactions, Enzymes, and Biochemical Genetics.”
1950- Reports of primaquine – caused hemolysis in individual who were
G6PD deficient.

5. Basics of genetics
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• The human genome contains more than 3 billion nucleotide base pairs, which code for
approximately 20,000 protein-coding genes.
• Two purine nucleotide bases,
adenine (A) and guanine (G),
• Two pyrimidine nucleotide bases,
cytosine (C) and thymidine (T),
• With purines and pyrimidines always pairing together as A-T and C-G in the two
strands that make up the DNA double-helix.
• Most nucleotide base pairs are identical from person to person, with only 0.1%
contributing to individual differences.

6. Basics of genetics
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• According to the central dogma when one strand of DNA is transcribed into RNA and
translated to make proteins, three consecutive nucleotides form a codon.
• Each codon specifies an amino acid or amino acid chain termination.
• For example, the nucleotide sequence, or codon, GGA specifies the amino acid
glycine.
• The genetic code has substantial redundancy, in that two or more codons code for the
same amino acid. For example, GGC, GGG, and GGT also code for glycine.
• Amino acids are the basic constituents of proteins, which mediate all cellular functions.
Only 20 different amino acids, in various arrangements, form the basic units of all the
proteins in the human body.

7. Basics of genetics
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• A gene is a series of codons that specifies a particular protein.
• Genes contain several regions: Exons that encode for the final protein,
Introns that consist of intervening noncoding regions
Regulatory regions that control gene transcription
• In most cases, an individual carries two alleles, one from each parent, at each gene
locus.
• An allele is defined as the sequence of nucleic acid bases at a given gene chromosomal
locus.
• Two identical alleles make up a homozygous genotype, and two different alleles make
up a heterozygous genotype.
• A phenotype refers to the outward expression of the genotype.

8. VED PATEL 8
Structure of gene

9. Type of genetic variations
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• Genetic variations occur as either rare defects or polymorphisms.
• Polymorphisms are defined as variations in the genome that occur at a frequency of at
least 1% in the human population.
• For example, the genes encoding the CYP enzymes 2A6 2C9, 2C19, 2D6, and 3A4 are
polymorphic, with functional gene variants of greater than 1% occurring in different
racial groups.
• In contrast, rare mutations occur in less than 1% of the population and cause inherited
diseases such as cystic fibrosis, hemophilia, and Huntington's disease.
• Common diseases, such as essential hypertension and diabetes mellitus, are polygenic
in that multiple genetic polymorphisms in conjunction with environmental factors
contribute to the disease susceptibility.

10. VED PATEL 10
• Single-nucleotide polymorphisms abbreviated as SNPs and pronounced "snips," are the
most common genetic variations in human DNA, occurring once approximately every
300 base pairs.
• More than 20 million SNPs have been mapped thus far in the human genome.
• SNPs occur when one nucleotide base pair replaces another.
• Thus, SNPs are single-base differences that exist between individuals.
• Nucleotide substitution results in two possible alleles. One allele, typically either the most
commonly occurring allele or the allele originally sequenced, is considered the wild type,
and the alternative allele is considered the variant allele.
• SNPs such as this that result in amino acid substitution are referred to as
nonsynonymous. SNPs that do not result in amino acid substitution are called
synonymous, which in many cases are silent.

11. 11
Martínez, M.F., Quiñones, L.A. (2018). Relationship Between Pharmacokinetics and Pharmacogenomics and Its Impact on Drug
Choice and Dose Regimens. In: Talevi, A., Quiroga, P. (eds) ADME Processes in Pharmaceutical Sciences. Springer

12. VED PATEL 12
Nucleotide sequence of the β2-adrenergic receptor gene from codons 13 through 19.
(A) Nucleotide sequence of the wild-type allele with adenine (A) at nucleotide position 46 (underlined) located in codon
16 of the β2-adrenergic receptor gene. Arginine (Arg), with an average. The AGA codon designates the amino acid
frequency of 39% in the human population. (B) Nucleotide sequence of the variant allele with guanine (G) at
nucleotide position 46 (underlined), located in codon 16. The GGA codon designates the amino acid glycine (Gly),
which occurs at an average frequency of 61%.
• Alterations in receptor downregulation on prolonged exposure to β2-receptor agonists.

13. Other types of genetic variations
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• Insertion-deletion polymorphisms, in which a nucleotide or nucleotide sequence is
either added to or deleted from a DNA sequence.
• Tandem repeats, in which a nucleotide sequence repeats in tandem (eg, if "AG" is
the nucleotide repeat unit, "AGAGAGAGAG" is a five-tandem repeat).
• Frameshift mutation, in which there is an insertion/deletion polymorphism, and the
number of nucleotides added or lost is not a multiple of 3, resulting in of the gene's
reading frame.
• Defective splicing, in which an internal polypeptide segment is abnormally
removed, and the ends of the remaining polypeptide chain are joined.
• Aberrant splice site, in which processing of the protein occurs at an alternate site.
• Premature stop codon polymorphisms, in which there is premature termination of
the polypeptide chain by a stop codon.
• Copy number variants, in which entire copies of genes or gene segments more than
1 kb in size are duplicated, deleted, or rearranged.

14. Polymorphism in genes of drug metabolic enzymes.
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• Polymorphisms in the drug-metabolizing enzymes represent the first recognized
and, so far, the most documented examples of genetic variants with consequences in
drug response and toxicity.
• There are 70 drugs that include pharmacogenetic information related to
polymorphisms in drug-metabolizing enzymes that contribute to variable drug
response.
• Currently, 57 different CYP isoenzymes have been documented to be present In
humans, with 42 involved in the metabolism of exogenous xenobiotics and
endogenous substances such as steroids and prostaglandins.
• Fifteen of these isoenzymes are known to be involved in the metabolism of drugs,
but significant interindividual variabilities in enzyme activity exist as a result of
induction, inhibition, and genetic inheritance.

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• Functional genetic polymorphism has been discovered for CYP2A6, CYP2B6,
CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
Martínez, M.F., Quiñones, L.A. (2018). Relationship Between Pharmacokinetics and Pharmacogenomics and Its Impact on Drug
Choice and Dose Regimens. In: Talevi, A., Quiroga, P. (eds) ADME Processes in Pharmaceutical Sciences. Springer

16. Single gene PK disorders
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Pseudocholinesterase
deficiency
Pseudocholinesterase is a plasma enzyme produced in the liver that is
responsible for the metabolism of common muscle relaxants, including
succinylcholine and mivacurium.
• side effect of certain medications
• prolonged muscular paralysis
Acute intermittent
porphyria
Acute intermittent porphyria (AIP) is a pharmacogenetic disease caused
by a porphyrin metabolic defect characterized by a lack of
porphobilinogen deaminase and a rise in the activity of delta-
aminolevulinic acid synthase—two essential enzymes required for heme
production.
• stomach discomfort, vomiting, muscular weakness, constipation, and
neuropsychiatric symptoms during an episode.
• Clinical episodes are produced by many drugs (including barbiturates,
antiseizure drugs, and sulfonamide antibiotics)

17. VED PATEL 17
Drug acetylation
deficiency
• Two genes (NAT 1) and (NAT 2) are now known to control N-acetyl
transferase (NAT), with NAT 2 A and B accounting for clinically
significant metabolic variance
• Caffeine, isoniazid, nitrazepam, and sulfonamides are among the
many common medications that are acetylated.

18. 18
Applied Biopharmaceutics & Pharmacokinetics, 7e, Leon Shargel, Andrew B.C. Yu
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19. CYP2D6
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• It is responsible for the metabolism Of as much as 25% Of commonly prescribed
drugs
• Polymorphisms in the CYP2D6 gene are the best characterized among all of the
CYP variants.
• It is estimated that approximately 10% of the Caucasian population, 1% of the
Asian population, and between 0% and 19% of the African population have a PM
phenotype of CYP2D6 (McGraw and Waller, 2012), resulting in increased plasma
concentration of the parent drug due to decreased metabolic clearance.

20. 20
Y. W. Francis Lam,, Chapter 1 - Principles of Pharmacogenomics: Pharmacokinetic, Pharmacodynamic, and Clinical Implications, Pharmacogenomics
(Second Edition), Academic Press, 2019, Pages 1-53, ISBN 9780128126264
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21. VED PATEL 21

22. VED PATEL 22

23. CY1A2
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• CYP1A2 activity varies widely with genetic polymorphisms contributing to
observed differences in levels of gene expression.
• CYP1A2 is responsible for the metabolism of about 5% of marketed drugs
including fluvoxamine, clozapine, olanzapine, and theophylline.
• Approximately 15% of the Japanese, 5% of the Chinese, and 5% of the Australian
populations are classified as CYPIA2 poor metabolizers.
• The most frequent allelic variant is CYPIA2*1F, which results in an increased
expression caused by an SNP in the upstream promoter region.
• Enhanced enzyme levels are thought to cause faster substrate clearance, which has
been associated with treatment failures for clozapine in smokers with the *IF allele
(Eap et al, 2004).
• CYPIA2*1C is also an SNP in the upstream promoter region that results in
decreased enzyme expression and has a prevalence up to 25% in Asian populations
(McGraw and Waller, 2012).

24. CYP2C9
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• CYP2C9 has at least 30 different allelic variants with the two most common
being CYP2C9*2 and *3.
• Both of these variants result in reduced CYP2C9 activity and are carried by
about 35% of the Caucasian population.
• CYP2C9 is a major contributor to the metabolism of the narrow therapeutic
index blood thinner warfarin.
• When a patient has one of these two polymorphisms, the dose of warfarin
needed for clinically relevant anticoagulation is generally much less since drug
clearance is reduced.

25. VED PATEL 25

26. CYP2C19
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• CYP2C19 is a highly polymorphic drug-metabolizing enzyme with at least 30
variants reported
• Polymorphisms in CYP2C19 result in variable drug response to clopidogrel and
several antidepressants.
• The PM phenotype is often the result of two null alleles, CYP2C19*2, and *3.
• Both alleles produce truncated, non-functional CYP2C19 through the
introduction of a stop codon.
• The allelic frequency of CYP2C19*2 has been shown to be 15% in Africans,
29%—35% in Asians, 12%—15% in Caucasians, and 61% in Oceanians.
• CYP2C19*3 is mainly found in Asians (596—9%) with very low frequency in
Caucasians (0.5%)

27. VED PATEL 27
EX-
• IMs and PMs of CYP2C19 may have reduced response to the antiplatelet agent
clopidogrel. This is because clopidogrel is a prodrug that requires conversion via
CYP2C19 to its active form, as shown in In IMs and PMs, clopidogrel may be less
effective at inhibiting platelet aggregation and preventing cardiovascular events
than in EMs.
• Patients that have this UM phenotype are either heterozygous or homozygous for
CYP2C19*17.
• Carriers of this allele are associated with higher risk for bleeding due to the
increased metabolism of clopidogrel to the active metabolite (Sibbing et ai, 2010).

28. CYP3A4
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• CYP3A4 is the most abundant CYP450 in the liver and metabolizes over 50% of
the clinically used drugs.
• In addition, the liver expression of CYP3A4 is variable between individuals.
• To date, over 20 allelic variants of CYP3A4 have been identified.
• Despite the large number of variants, there is limited data demonstrating any
clinical significance for CYP3A4 substrates.
• The CYP3A4*2 allele has a non-synonymous SNP that is found in about 2.7% of
the Caucasian population and has some decreased clearance for the calcium
channel blocker nifedipine

29. OTHERS
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32. UTILITY EXAMPLES(Clinical Pharmacogenetics Implementation
Consortium (CPIC) recommendations)
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33. VED PATEL 33

34. VED PATEL 34

35. PGX of phase 2 enzymes
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Inheritance and Drug Response, Richard Weinshilboum, M.D., N Engl J Med 2003; 348:529-537.
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36. There are also polymorphism in Drug transporters
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• MDR1 (P-Glycoprotein)
• ABC Transporters
• Solute Carrier Transporters

37. THANK YOU
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