Pharmacogenetics involves studying genetic variations that lead to differences in individual drug responses. The goals are to optimize drug therapy and limit toxicity based on a person's genetic profile by choosing the best drug, dose, and duration for that individual. Genetic variations can occur as single nucleotide polymorphisms, which are single base pair differences between individuals. Polymorphisms in genes encoding drug-metabolizing enzymes, such as CYP2D6 and CYP2C9, are clinically significant as they can result in poor, intermediate, extensive, or ultrarapid metabolism of certain drugs. This can impact treatment outcomes and risk of adverse effects.

1. Pharmacogenetics

2. definition
• 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.

4. • 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.
• Clinical implementation of pharmacogenetics is beginning to emerge
in other therapeutic areas, such as cardiology, neurology, pain
management, and infectious disease.

5. GENETIC CONCEPTS
• 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),
• are present in DNA,
• 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. • 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. • 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, and 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. TYPES OF GENETIC VARIATIONS
• 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.

9. • 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.

10. Source: Pharmacogenetics, Pharmacotherapy: A Pathophysiologic Approach, 10e
Citation: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e; 2017 Available
at: http://accesspharmacy.mhmedical.com/content.aspx?sectionid=146077703&bookid=1861&Resultclick=2 Accessed: March 29, 2017
Copyright © 2017 McGraw-Hill Education. All rights reserved
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%. Although the
Arg16 polymorphism occurs less commonly than the Gly16 polymorphism, it is referred to as the wild type because it was identified first.

11. • A SNP may result in amino acid substitution, which may or may not alter the
function of the encoded protein.
• For example, guanine (G) is substituted for adenine (A) at nucleotide 46 in the β2-
adrenergic receptor gene.
• This results in the substitution of glycine for arginine at amino acid position
(codon) 16 and alterations in receptor downregulation on prolonged exposure
to β2-receptor agonists.
• 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.

12. Other examples of genetic variants include:
• 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 disruption 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 (specific sequence of three nucleotides that do not code for an
amino acid but rather specify polypeptide chain termination).
• Copy number variants, in which entire copies of genes or gene segments more than 1 kb in size
are duplicated, deleted, or rearranged.

13. POLYMORPHISMS IN GENES FOR DRUG-
METABOLIZING ENZYMES
• 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
•

14. Source: Pharmacogenetics and Drug Metabolism, Applied Biopharmaceutics & Pharmacokinetics, 7e
Citation: Shargel L, Yu AC. Applied Biopharmaceutics & Pharmacokinetics, 7e; 2016 Available at:
http://accesspharmacy.mhmedical.com/content.aspx?sectionid=100672633&bookid=1592&jumpsectionID=100672692&Resultclick=2
Accessed: April 03, 2017
Copyright © 2017 McGraw-Hill Education. All rights reserved
Drug-metabolizing enzymes that exhibit clinically relevant genetic polymorphisms. Essentially all of the major human enzymes responsible for modification
of functional groups (classified as phase I reactions [left]) or conjugation with endogenous substituents (classified as phase II reactions [right]) exhibit
common polymorphisms at the genomic level; those enzyme polymorphisms that have already been associated with changes in drug effects are separated
from the corresponding pie charts. The percentage of phase I and phase II metabolism of drugs that each enzyme contributes is estimated by the relative
size of each section of the corresponding chart. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CYP, cytochrome P-450; DPD,
dihydropyrimidine dehydrogenase; NQO1, NADPH, quinone oxidoreductase or DT diaphorase; COMT, catechol O-methyltransferase; GST, glutathione S-
transferase; HMT, histamine methyltransferase; NAT, N-acetyltransferase; STs, sulfotransferases; TPMT, thiopurine methyltransferase; UGTs, uridine 5′-
triphosphate glucuronosyltransferases. (From Evans and Relling, 1999, with permission.)

15. Cytochrome P450 Enzymes
• 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.
• Functional genetic polymorphism has been discovered
for CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, and their
impacts on drug therapy are described hereunder.

16. CYP2D6
• 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.
• Over the years, at least 100 gene variants and 120 alleles have been identified in
the CYP2D6 gene
• More specifically, different studies showed that the CYP2D6 phenotypes of
extensive metabolizer (EM) carrying two functional alleles and poor metabolizer
(PM) carrying two nonfunctional alleles could be predicted with up to 99%
confidence with six genotypic variants.

17. Enzyme Drug Substrate
CYP2D6 Analgesics (codeine, tramadol)
Antiarrhythmics (propafenone, flecainide)
Atomoxetine
Antipsychotics (haloperidol, perphenazine,
thioridazine)
β-blockers (metoprolol, carvedilol)
Perhexiline
Selective serotonin reuptake inhibitors (fluoxetine,
paroxetine, sertraline)
Tamoxifen
Tricyclic antidepressants (desipramine,
nortriptyline, amitriptyline, imipramine)

18. • CYP2D6*1 is considered the wild-type variant and exhibits normal
enzyme activity.
• CYP2D6*2 has the same activity as CYP2D6*1 but is capable of
duplication or amplification.
• Both these variants are present in EMs.

19. • The two null variants, CYP2D6*4 (c.1846G>A, defective splicing)
and CYP2D6*5 (gene deletion), are predominantly found in white PMs (5%-
10% of population) and result in an inactive enzyme and absence of
enzyme, respectively.
• other variants are also associated with lower enzyme activity in the
intermediate metabolizers (IMs) phenotype (carriers of one nonfunctional
allele and one allele with diminished activity).
• In addition to *2, gene duplication or amplification had been documented
for *1,*4, *6, *10, *17, *29, *35, *41, *43, and *45 variants,with resultant
higher enzyme activity in the ultrarapid metabolizer (UM) phenotype
(carriers of multiple copies of functional alleles).

20. Examples
• When a patient with a PM phenotype is administered a tricyclic
antidepressant, the increased plasma concentration increases the
potential for CNS depression.
• Tamoxifen has an active metabolite (endoxifen) produced by CYP2D6
that is thought to be responsible for much of its antiestrogenic
activities. The patient with the PM phenotype would not metabolize
tamoxifen to the active metabolite and, therefore, does not benefit
from clinically relevant endoxifen concentrations.

21. • Active drugs like the tricyclic antidepressant amitriptyline may require
doses several-fold higher than standard doses to achieve therapeutic
activity when the patient is a UM.
• Codeine is converted to morphine by a CYP2D6 O-demethylation
reaction to provide analgesic effects, and morphine-associated
toxicity has been reported after codeine administration in patients
who are UM
• black box warning to highlight the risk of death in children with
CYP2D6 UM phenotypes

22. • The UM phenotype is found in Caucasian populations (1%–10%), but
is more common in others such as Saudi Arabians (20%) and
Ethiopians (29%) (Samer et al, 2013).

23. Clinically Important Genetic Polymorphisms of Drug Metabolism
and Transporters That Influence Drug Response

25. CYP1A2
• 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 CYP1A2 poor
metabolizers.

26. • The most frequent allelic variant is CYP1A2*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 *1F allele (Eap et al, 2004).
• CYP1A2*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).

27. CYP2C9
• 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.

28. • If the dose of warfarin is not appropriately lowered, then there is an
increased risk of bleeding.
• There are several other drugs affected by the polymorphisms of CYP2C9,
including many nonsteroidal anti-inflammatory drugs, sulfonylureas,
angiotensin II receptor antagonists, and phenytoin.
• For each of these, the CYP2C9*2 and *3 polymorphisms result in higher
plasma concentrations but, because of their high therapeutic indices
(except phenytoin), do not usually result in adverse effects. In the case of
phenytoin, the polymorphisms result in drug accumulation and require
dose reduction to prevent toxicity (ie, dizziness, nystagmus, ataxia).

30. CYP2C19
• 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, nonfunctional 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 (5%–9%) with very low frequency in Caucasians (0.5%)

31. • The CYP2C19 PM phenotype results in a lack of efficacy for the
antiplatelet prodrug clopidogrel.
• For activation, clopidogrel requires a two-step metabolism by several
different CYP450 with CYP2C19 being a significant contributor.
• Studies have demonstrated, and the FDA has added to the label, that
deficiencies in CYP2C19 activity may result in the increased risk of
adverse cardiovascular outcomes because the PM does not activate
clopidogrel

32. • With omeprazole the opposite occurs since metabolism inactivates the
drug.
• The PM phenotype results in higher plasma concentrations, larger AUC
values, and greater efficacy in lowering gastric pH than extensive
metabolizers with CYP2C19*1 alleles.
• The higher plasma concentration of omeprazole is particularly useful in the
multiple-drug treatment of Helicobacter pylori. In the PM patients treated
with omeprazole, the H. pylori eradication rate is higher when they have
one or more of the null alleles (Shi and Klotz, 2008).

33. • The CYP2C19*17 allele results in a gain of function and, therefore, has more metabolic
capacity than the wild-type enzyme, CYP2C19*1, because of an SNP in the upstream
noncoding region that induces transcription.
• 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 al, 2010).
• These examples demonstrate that both loss and gain of function alleles can have
significant effects on patient outcomes depending upon the blood levels and activity of
the parent drug and the metabolite.

35. CYP3A4
• 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.
• Some of the variability may be caused by allelic variants that influence the upstream noncoding
region of the gene, specifically in CYP3A4*1B allele, which may influence gene expression,
although the exact transcription factor binding site has not been identified (Sata et al, 2000).

36. • 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
• The effects of the polymorphisms in CYP3A4 are still under
investigation but currently there are no null phenotypes.

37. Dihydropyrimidine dehydrogenase (DPD)
• DPD is the first reduction and rate-limited step in breakdown of the pyrimidine
nucleic acids and their analogs.
• Polymorphisms in DPD result in a loss of enzymatic activity leading to the
accumulation of the chemotherapeutic agent 5-flourouracil (5-FU), which leads to
significant toxicity including leukopenia, thrombocytopenia, and stomatitis.
• It is estimated that approximately 3%–5% of population has low or deficient DPD
activity.
• There are three alleles, each with low frequency, that appear to account for the
majority of the deficient DPD activity observed and more than 20% of the serious
toxicity observed with 5-FU administration.

38. • DPYD*2A is the most common allelic variant, although the exact
frequency is not clear.
• This variant results in a nonfunctional enzyme due to a point
mutation that creates an exon skipping splice variant.
• DPYD*13 and c.2846A>T variants are non-synonymous SNPs that
decrease the activity of the DPD produced.

39. Thiopurine S-methyltransferase
• Thiopurine drugs including 6-mercaptopurine (MP) and azathioprine
are used for their anticancer and immunosuppressive properties but
can have significant adverse effects including myelosuppression.
• The phase II metabolizing enzyme thiopurine S-methyltransferase
(TPMT) is involved in the degradation of thiopurine drugs and TPMT
polymorphisms account for about one-third of the variable responses
to MP and azathioprine.

40. • While TPMT alone only explains one-third of the variability, other
factors are known to contribute, which highlights the challenge and
multifactorial nature of personalized medicine to account for
intraindividual differences.
• At least twenty-eight allelic variants in the coding and splicing region
of TPMT have been identified with most of the null phenotypes being
associated with TPMT*2, TPMT*3A, and TPMT*3B alleles resulting in
non-synonymous mutations that lead to the production of an
unstable enzyme and reduced activity overall.

41. • The loss of TPMT function is present in about 5% of the Caucasian
population and results in accumulation of MP leading to an increased
risk for adverse effects like leukopenia
• Although not well understood, variations in the promoter region for
TPMT can also account for some of the observed differences in
expression and susceptibility for adverse effects.
• The remaining variability may be accounted for with numerous other
factors including some genetic and some environmental.

42. N-Acetyltransferase
• N-acetyltransferase (NAT) was identified as a polymorphic enzyme through
phenotypic observations of fast or slow acetylators of the anti-tuberculosis drug,
isoniazid (Evans and White, 1964).
• There are two different human genes, NAT1 and NAT2, that code for functional
NAT activity.
• While both NAT1 and NAT2 are polymorphic, the fast and slow acetylator
phenotype is associated with the NAT2 gene.
• The slow acetylator phenotype is found in about 50% of Caucasians, 90% of
Arabs, and 10% of Japanese populations (Green et al, 2000).

43. • Several NAT2 alleles, *5, *6, *7, *10, *14, and *17, are either null
genes or encode of defective enzymes that contribute to the slow
phenotype (Pharmacogenetics Knowledge Base, 2014).
• Patients that are slow metabolizers of isoniazid exhibit increased
blood levels of the drug, which results in an increased incidence of
neurotoxicity.

44. • The metabolism of both procainamide and hydralazine is also
dependent upon the activity of NAT2 such that slow metabolizers are
associated with an increased risk of lupus erythematosus (Chen et al,
2007).

45. POLYMORPHISMS IN DRUG TRANSPORTER GENES
• Genetic variations for drug transport proteins may affect the distribution of
drugs that are substrates for these proteins and alter drug concentrations
at their therapeutic sites of action.
• P-glycoprotein is one of the most recognized of the drug transport proteins
that exhibit genetic polymorphism.
• P-glycoprotein is an energy-dependent transmembrane efflux pump
encoded by the ABCB1 gene (also known as the multidrug resistance 1
gene), which is a member of the adenosine triphosphate (ATP)-binding
cassette (ABC) transporter superfamily.

46. • P-glycoprotein was first recognized for its ability to actively export
anticancer agents from cancer cells and promote multidrug resistance to
cancer chemotherapy.
• Later, it was discovered that P-glycoprotein is also widely distributed on
normal cell types, including
• intestinal enterocytes,
• hepatocytes,
• renal proximal tubule cells, and
• endothelial cells lining the blood–brain barrier.
• At these locations, P-glycoprotein serves a protective role by transporting
toxic substances or metabolites out of cells.

47. • P-glycoprotein also affects the distribution of some
nonchemotherapeutic agents, including
• digoxin,
• immunosuppressants cyclosporine and tacrolimus, and
• antiretroviral protease inhibitors .

48. Source: Pharmacogenetics, Pharmacotherapy: A Pathophysiologic Approach, 10e
Citation: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 10e; 2017 Available
at: http://accesspharmacy.mhmedical.com/content.aspx?sectionid=146077703&bookid=1861&Resultclick=2 Accessed: April 10, 2017
Copyright © 2017 McGraw-Hill Education. All rights reserved
Active transport of drugs out of the cell by P-glycoprotein.

49. • Increased intestinal expression of P-glycoprotein can limit the
absorption of P-glycoprotein substrates, thus reducing their
bioavailability and preventing attainment of therapeutic plasma
concentrations.
• Conversely, decreased P-glycoprotein expression may result in
supratherapeutic plasma concentrations of relevant drugs and drug
toxicity.

50. • Numerous SNPs and insertion/deletion polymorphisms have been
identified in the promoter and exon regions of the ABCB1 gene and
while there is evidence that ABCB1 genotype influences response to
digoxin and other P-glycoprotein substrates,
• the evidence has not reached a level sufficient for clinical
implementation.

51. • Other examples of polymorphic drug transporter proteins include the
organic anion transporter (OAT) and organic cation transporter (OCT),
both members of the solute carrier (SLC) transporter family.
• The SLC01B1 gene encodes for OAT polypeptide B1, which mediates
the uptake of β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA)
reductase inhibitors (statins) into the liver.

52. • The reduced function SLC01B1 c.521T > C SNP, resulting in the p.Val174Ala
substitution and contained within the SLC01B1*5 haplotype, has been
associated with higher statin concentrations.
• Each copy of the C allele increased the risk for myopathy
with simvastatin 80 mg/day by 4.5-fold in a genome-wide association study
(GWAS)
• In a replication cohort of patients treated with simvastatin 40 mg/day, the
relative risk for myopathy was 2.6 per copy of the 521C allele. The
association between the 521C allele and statin-induced myopathy was
further confirmed in later studies.

53. ROLE OF CLINICIANS
• Pharmacogenetics provides opportunities to improve drug therapy
outcomes, but requires that clinicians be knowledgeable about genetic
determinants of drug response.
• A challenge to pharmacogenomics implementation is that genotype needs
to be considered in the context of important clinical factors, such as age,
body size, and concomitant drug therapy, in making drug therapy decisions.
• Another challenge is that multiple genetic variants may affect response to
some drugs. For example, both the CYP2C9 (drug metabolism) and VKORC1
(target site) genes contribute to response to warfarin.

54. • Pharmacists are in a unique position in dealing with the complexities
of the drug-decision process in the era of pharmacogenetics.
• Pharmacists will be in key positions to play valuable roles on
multidisciplinary teams charged with interpreting genetic test results
and choosing the most appropriate drug for a given patient based on
genotype. Thus, it will be essential for pharmacists to stay abreast of
significant pharmacogenetic discoveries and guideline updates.

55. Example test
• Roche AmpliChip P450 Array.
• Approved by the FDA
• determines genotypes for alleles of selected CYP genes —including
CYP2D6 and CYP2C19

56. • The AmpliChip CYP450 Test is based on five major processes:
• PCR amplification of purified DNA;
• fragmentation and labeling of the amplified products;
• hybridization of the amplified products to a microarray and
• staining of the bound products; scanning of the microarray; and
determination of the CYP450 genotype and predicted phenotype.

57. PHARMACOGENETIC DRUG LABELING AND
GUIDELINES
• More than 120 drugs now contain pharmacogenetic information in
their FDA-approved labeling.
• The pharmacogenomic information appears in various sections of the
label. For example, the information appears as a Boxed Warning for
clopidogrel and carbamazepine because of the serious consequences
of genetic variation on drug response.

58. • In the case of warfarin, mercaptopurine, and irinotecan, the
pharmacogenomic information appears in the drug dosing section.
• Guidelines are now available to assist with translating genotype
results into actionable prescribing decisions for a number of drugs.
• Among these are guidelines from the Clinical Pharmacogenetics
Implementation Consortium (CPIC).
• https://cpicpgx.org/

59. • CPIC is an international collaboration of individuals from academic
centers, clinical institutions, and pharmacy benefits management
with expertise in pharmacogenomics or laboratory medicine that
provides consensus-based guidelines on how to use genetic test
results to optimize pharmacotherapy.
• The CPIC guidelines, in addition to other pharmacogenetic
information, are freely available through the Pharmacogenomics
Knowledge Base (PharmGKB).

60. Attached tables
• TABLE e5-3_Examples of Drugs with Pharmacogenomic Labeling
• TABLE e5-4_Guidelines from the Clinical Pharmacogenetics
Implementation Consortium