Importance of Pharmacogenomics in the Personalized

Medicine.
Pharmacogenetics:
The study of genetic causes of individual variations of DNA and RNA characteristics as related to
the response to drug.

Pharmacogenomics:
The branch of science concerned with the identification of the genetic attributes of an
individual that lead to variable responses to drug.

Personalized medicine:
Personalized medicine is based on using an individual's genetic profile to make the best
therapeutic choice by facilitating predictions about whether that person will benefit from a
particular medicine or suffer serious side effects. Drugs are generally tested on a large
population of people and the average response is reported. This sort of evidence-based
medicine (that is, medical decision making based on empirical data) relies on the law of
averages; personalized medicine, on the other hand, recognizes that no two patients are alike.

Why is genomic information helpful?

Each gene provides the blueprint for the production of a certain protein in the body. A
particular protein may have an important role in drug treatment for one of several reasons,
including the following:

 The protein plays a role in breaking down the drug.

 It helps with the absorption or transport of the drug.

 The protein is the actual target of the drug.

 It has some role in a series of molecular events triggered by the drug.

When researchers compare the genomes of people taking the same drug, they may discover
that a set of people who share a certain genetic variation also share a common treatment
response, such as:

 A greater risk of side effects

 Severe side effects at relatively low doses

 The need for a higher dose to achieve a therapeutic effect

 No benefit from the treatment

 A greater or more likely benefit from the treatment

 The optimal duration of treatment

This kind of treatment information is currently used to improve the selection and dosage of
drugs to treat a wide range of conditions, including cardiovascular disease, lung disease, HIV
infection, cancer, arthritis, high cholesterol and depression.

In cancer treatments, there are two genomes that may influence prescribing decisions — the
genome of the person with cancer and the genome of the cancerous (malignant) tumor.

There are many causes of cancer, but most cancers are associated with damaged DNA that
allows cells to grow unchecked. The "incorrect" genetic material of the unchecked growth —
the malignant tumor — is really a separate genome that may provide clues for treatment. For
example, the drug trastuzumab (Herceptin) is most likely to be effective against breast cancer
cells that have an extra copy of a particular gene and high levels of the gene's corresponding
protein.

Why need personalized medicine?

Every years in the USA 2 million people die due to adverse drug effects. Drug efficacy only in
60% of the population. Other 40% have poor drug effects or no effect at all.

Pharmacogenomics shows how genes determine individual variability to drug response and for
pharmacists it would be easy to predict how a patient may respond to drug, with the help of a
genetic test before prescribing a drug. Some dose does not produce the same concentration
among patients due to inter patient difference in absorption and metabolism. Genetic
variations have influence on efficacy and toxicity of drug. 0.1% difference in genome influences
the response to drugs.
The Body of enzyme production in genetics is playing an important role. Cytochrome P450
super family of enzymes. It is important drug metabolizing enzymes. Bioactivation and
metabolism of approximately 75% of drug gives CYPs prominence in pharmacogenetics
research.

Drug Effect on Drugs:

Hypertension Drugs (ACE inhibition) 10-20%

Heart failure drugs (Beta Blockers) 15-25%

Anti Depressants 20-50%

Cholesterol Drugs (Statins) 30-70%

Asthma Drugs (Beta-2-agonists) 40-70%

CYPTOCROME P450
It is host of enzyme that use iron to oxidize things. It is found in liver and small intestine. There
are thousand different cytochromes . Although the no. in man is only about 50.

There is high expression of CYP2D6 in many persons of Ethiopian and Saudi Arabian
origin.CYP2D6 is not inducible, so these people have developed a different strategy to cope
with the high load of toxic alkaloids in their diet. These CYPs therefore chew up a variety of
drugs, making them ineffective- many antidepressant and neuroleptics.

CYTOCHROME P2D6 deficiency:

 Many individuals lack functional 2D6.

 These subjects will be predisposed to drug toxicity caused by antidepressant and
neuroleptics

The most commonly prescribed anticoagulant drug is WARFARIN.The patient who r may be
resistant are needed higher dose of warfarin to prevent strokes and sensitive patient needs
lower dose to prevent CNS bleeds.Warferin is metabolized by cytochrome p450,
CYP2C9.warferin metabolism involves vitamin-k epoxide redutase.

A person who have a deficiency in plasma cholinesterase or its activity. That reason an inherited
abnormality of succinylcholine metabolism.Africans have a glucose-6-phosphate
dehydrogenase deficiency that reason they are suffer drug induced haemolysis.

Acute Coronary syndrome in Russian patient:

The aim of this study is to investigate the frequency of CYP2C19*2, *3 allelic variants,
associated with poor response to clopidogrel, and CYP2C19*17, associated with excessive
response to clopidogrel, in patients with acute coronary syndrome (ACS) from Siberia and
Moscow regions of Russia.
The study included 512 ACS patients who were subsequently treated with coronary arterial
stenting. The subjects assigned were from the cities of Central (Novosibirsk, Kemerovo), Eastern
(Irkutsk), Northern (Surgut) Siberia regions and from Moscow region. The mean age of patients
enrolled was 63.9±10.9 years. Among the assigned subjects, the proportion of men accounted
for 80% and women 20%.
 According to the results obtained in the present study, from 16% up to 27.5% of patients in
different regions of Russia have at least one CYP2C19 “poor metabolizer” (PM) allele variant
affecting clopidogrel metabolism and, therefore, suppressing its antiplatelet
activity. CYP2C19*17 allele variant was identified with the frequency of 15.4% up to 33.3%. The
study revealed the presence of statistically significant differences in CYP2C19*3 allele frequency
between the Russian ethnic group patients from Eastern and Central Siberia (p=0.001; odds
ratio=1.05 [95% confidence interval 1.01–1.09]).
 The study revealed statistically significant differences between the allele frequencies in Eastern
and Central Siberia, which can probably be caused by a considerable number of Buryats
inhabiting Eastern Siberia.

Influence on Carbamazepine Treatment:

 Carbamazepine (CBZ) is an effective anticonvulsant that can sometimes cause hypersensitivity
reactions that vary in frequency and severity. Strong associations have been reported between
specific human leukocyte antigen (HLA) alleles and susceptibility to CBZ hypersensitivity
reactions. Screening for HLA-B*15:02 is mandated in patients from South East Asia because of a
strong association with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN). HLA-A*31:01 predisposes to multiple phenotypes of CBZ hypersensitivity including
maculopapular exanthema, hypersensitivity syndrome, and SJS/TEN in a range of populations
including Europeans, Japanese, South Koreans and Han Chinese, although the effect size varies
between the different phenotypes and populations. Between 47 Caucasians and 67 Japanese
patients would need to be tested for HLA-A*31:01 in order to avoid a single case of CBZ
hypersensitivity. A cost-effectiveness study has demonstrated that HLA-A*31:01 screening
would be cost-effective. Patient preference assessment has also revealed that patients prefer
pharmacogenetic screening and prescription of alternative anticonvulsants compared to
current standard of practice without pharmacogenetic testing. For patients who test positive
for HLA-A*31:01, alternative treatments are available. When alternatives have failed or are
unavailable, HLA-A*31:01 testing can alert clinicians to 1) patients who are at increased risk of
CBZ hypersensitivity who can then be targeted for more intensive monitoring and 2) increase
diagnostic certainty in cases where hypersensitivity has already occurred, so patients can be
advised to avoid structurally related drugs in the future. On the basis of the current evidence,
we would favor screening all patients for HLA-A*31:01 and HLA-B*15:02 prior to starting CBZ
therapy.

How does pharmacogenomics work in practice?

An example of pharmacogenomics in treatment decisions is the use of a blood-thinning drug
called warfarin (Coumadin, Jantoven). If you have a blood clot, your treatment may include a
prescription for warfarin to treat the current clot and to prevent additional blood clots from
forming.

Your doctor's goal is to prescribe a dose that will be strong enough to prevent blood clotting but
not strong enough to cause adverse reactions, such as internal bleeding (hemorrhaging). The
window for the effective and safe dose of this drug for any person is relatively narrow.

Dosage has traditionally been based on such factors as weight, age, and kidney and liver
function, as well as a laboratory test to assess the blood-thinning effect of the drug in each
person. The dosing guidelines, although valuable, may have limited value in predicting the
outcome for every person.

In the early 2000s, studies comparing treatment outcomes with genomic data revealed that
genetic variation was associated with either an increased risk of hemorrhaging or with the need
for a higher dose to be effective.

Because of these findings, your doctor may use your genomic information to help guide
treatment decisions. A tissue sample swabbed from inside your cheek or a blood sample
provides cells for a laboratory test to decipher your genome.
Based on the results, your doctor may judge more accurately what dose of warfarin is likely to
be safe and effective for you or whether warfarin is even an appropriate treatment option.

So, “Right drug at the right dose in the right patient”.

Reference:
https://www.dovepress.com/pharmacogenomics-and-personalized-medicine-journal

https://www.mayoclinic.org/healthy-lifestyle/consumer-health/in-depth/personalized-
medicine/art-20044300

https://www.mayoclinic.org/healthy-lifestyle/consumer-health/in-depth/personalized-
medicine/art-20044300

A LANGE medical Book: Basic & Clinical Pharmacology – Author: Bertram G. Katzung