First [

year, ‫ب‬
Level 4

Pharmacogenomic

ACADMIC NUMBER: 442105812

MOHAMMED ALI ALMUTARID

DR. Shafi Habeeb MEDECINE COLLEGE

iNDEX:

1 What is pharmacogenomics:

2 Pharmacogenomic: precision medicine

3 Cancers, pharmacogenomic and using

to treatment
Toxicity prediction
4 Efficiency prediction
TARGETED THERAPIES IN THE
FUTURE

5 Pharmacogenomic: Personalized
Psychiatry

6 Conclusion
What is pharmacogenomics:

Pharmacogenomics is the use of genetic data to guide medicine and dose selection
on an individual basis. Its goal is to identify people who are more or less likely to
respond to a drug, as well as those who require a different dose of a treatment. It is
attempted to establish the genetic foundation of a person's drug response profile and
to anticipate the optimum treatment option for him or her. This has mostly been used
on individuals with known genetic defects so far, but the ultimate goal is 'personalized
treatment' on a large scale. However, a significant fraction of genetic variation is still
.unexplained for

A new infant has died from morphine poisoning of when his mother breastfed him
while using codeine, why? Because his mother has rapid metabolizer cytochrome-450
enzyme that metabolize codeine faster and increase the level of morphine which
expose the infant to toxic level when breastfeeding

In the postpartum phase, codeine is regularly used to relieve pain from episiotomy
and cesarian section. The safety of codeine and its pharmacologically active
metabolite, morphine, among breastfed newborns is of main concern because most
mothers begin nursing. Despite inadequate published research to support this
suggestion, the American Academy of Pediatrics and major authoritative manuals
identify codeine as compatible with breastfeeding. We describe a case of a full-term,
breastfed newborn who died in a way consistent with morphine overdose to highlight
the need for more research into codeine and morphine transfer into breast milk. The
production of the pharmacologically active opioid morphine was confirmed by
pharmacogenetic analysis of maternal drug biotransformation. To our understanding,
.this is the first case a breastfed baby has died from poisoning caused by breast milk
Pharmacogenomic: precision medicine

The ultimate goal of precision medicine is to precisely match each treatment action to
the patient's molecular profile. Cutting-edge sequencing technology have propelled
the research of human genetics during the last two decades, resulting in a better
knowledge of the connection between genetic variation and human health . The study
of genetics has been extensively applied in precision medicine, and
pharmacogenomics-informed pharmacotherapy, which tailors drug selection and dose
to the patient's genetic traits, is one of the developing uses. To present,
pharmacogenomic variation has been proven to play a role in therapeutic efficacy and
safety, allowing worldwide scientific consortia to develop treatment guidelines for the
clinical use of pharmacogenomics, However, pharmacogenomics' integration into
ordinary clinical care is still restricted. From basic pharmacogenomics research to
implementation, a number of significant barriers have been discovered. To improve
pharmacogenomic knowledge, more research into previously overlooked rare genetic
variations and validation of their functional and clinical impact through the
development of pre-clinical models and in silico technologies is needed. On the other
hand, continuing international coordinated initiatives to eliminate existing
impediments to pharmacogenomic implementation will bring new tools and insights
into pharmacogenomic clinical application, paving the road for widespread adoption
Eleven papers are published in this Special Issue, including multiple elements of
pharmacogenomics research and clinical application.

Genetic diversity in the expression and activity of drug metabolizing enzymes,

enzymes that can alter plasma drug concentrations, was the most relevant factor.
Werner Kalow of the University of Toronto, who studied butyrylcholinesterase
genetic variation and prolonged apnea after treatment with the muscle relaxant
succinylcholine and David Price Evans of Johns Hopkins University, who pursued
earlier reports of genetic variation in the N-acetylation of the antituberculosis drug
isoniazid, were among the early pioneers in pharmacogenomic research. Following
that, genetic variation in the thiopurine S-methyltransferase (TPMT) enzyme was
linked to potentially fatal myelosuppression following therapy with the anticancer and
immunosuppressant drugs mercaptopurine and azathioprine, which are TPMT
substrates, was reported as Genetic variation in another drug metabolizing enzyme,
cytochrome (CYP) P450 CYP2D6, , has been linked to differences in plasma
concentrations and therapeutic effects of several medications. These early examples
were discovered before genes were cloned and sequenced, and they were most often
demonstrated to be genetic through family studies using approaches similar to those
used by Mendel in the previous century when he performed his renowned breeding
studies by using peas. These early instances have withstood the test of time and are
now well known mechanistically, regardless of how primitive they may appear in the
post-Human Genome Project world.

Cancers, pharmacogenomic and using to treatment

Pharmacogenetics and pharmacogenomics (PGx) are fast expanding studies aimed at

elucidating the genetic basis for interindividual medication response variability. Many
anticancer medications have been subjected to PGx methods in the hopes of
identifying relevant inherited or acquired genetic variants that could predict patient
response to chemotherapy and targeted therapies. Many articles discuss recent
technological advances and new revolutionary massive sequencing technologies, as
well as their application to elucidate the genetic bases for interindividual drug
response and the development of biomarkers that can personalize drug treatments, in
.the field of cancer pharmacogenetics and pharmacogenomics

Molecular study of different important genes implicated in tumorigenic pathways is

now driving cancer patient treatment. Certain cancers, such as advanced non-small
cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations
and tyrosine kinase inhibitors (TKIs) or advanced colorectal cancer (CRC) with k-ras
.wild-type and anti-EGFR monoclonal antibodies (mAbs), require targeted therapy
*
Toxicity predictions

The finding of changes in drug metabolism linked to genomic variations in drug-

metabolizing enzymes like the cytochrome system was one of the first applications of
.SNP genotyping in cancer care

Other detoxification routes linked to SNP-based differences in drug metabolism have

been described, but these indicators have yet to gain therapeutic value in comparison
to the cytochrome gene system. As more candidate polymorphisms are discovered,
the pharmacogenetics approach's potential therapeutic relevance for predicting drug
.toxicity will be revealed
Drug Efficacy Prediction
Genotyping methods for predicting anticancer treatment success have lately become
.popular in a number of clinical contexts
Genotype resistance testing of HIV isolates has been shown to be useful in the clinic
and can help guide therapy decisions in individuals whose HIV RNA levels are rising.
Pretreatment genotyping on peripheral blood samples is now being used to determine
therapy for colorectal cancer patients based on the prediction of resistance associated
with particular genetic variants.

TARGETED THERAPIES IN THE FUTURE

Bevacizumab (AvastinTM) and cetuximab (ErbituxTM), both approved by the FDA
recently for the treatment of metastatic colorectal cancer, have been added to the list
of approved biologic (antibody) therapeutics and small-molecule drugs for the
treatment of hematologic malignancies and solid tumors. In both general usage and
published literature, the term "targeted therapy" has been defined in a variety of ways.
The most stringent meaning confines the word to medications for which the FDA has
approved a specific diagnostic test that must be done in order for the patient to be
.considered eligible for therapy (for example, imatinib, trastuzumab, and cetuximab)
Pharmacogenomic: Personalized Psychiatry

Following the successful conclusion of the Human Genome Project, it was expected
that fresh genetic discoveries would improve medical care in a rapid and fundamental
way. For example, it was believed that using patients' genetic markers,
pharmacological treatment response and treatment-related side effects would become
more predictable. However, progress has been far slower than planned so far
Part of the reason for this delay is that a person's response to pharmacotherapy is
multifactorial, involving multiple genes that interact with a variety of environmental
factors This is particularly difficult in psychiatric pharmacogenomic investigations,
because the underlying features are extremely complicated and varied. Furthermore,
it is unclear if existing pharmacogenomics knowledge contains the necessary and
Following the successful conclusion of the .sufficient information for clinical tests
Human Genome Project, it was expected that fresh genetic discoveries would improve
medical care in a rapid and fundamental way. For example, it was believed that using
patients' genetic markers, pharmacological treatment response and treatment-related
side effects would become more predictable. However, progress has been far slower
.than planned so far
Part of the reason for this delay is that a person's response to pharmacotherapy is
multifactorial, involving multiple genes that interact with a variety of environmental
factors [36]. This is particularly difficult in psychiatric pharmacogenomic
investigations, because the underlying features are extremely complicated and varied.
Furthermore, it is unclear if existing pharmacogenomics knowledge contains the
necessary and sufficient information for clinical tests as well as their applications
Nonetheless, pharmacogenomics knowledge is developing, and it may be possible in
the future to combine genomic data with other biological and clinical data to aid
decision-making in psychiatric care clinical tests.

Recent findings in pharmacogenomics of mood disorders have focused on the

treatment response to selective serotonin reuptake inhibitors (SSRIs) in MDD and the
treatment response to lithium in BPD, also various methodological options for
integrating genetic evidence into clinical therapy, as well as future direction
towards personalized psychiatry
 In conclusion

With the rapid evolution of genetic and genomic technologies revolutionizing our
approach to prognosis, screening, and targeting of therapies, the age of personalized
and predictive medicine is defining how clinical practice is evolving today and how it
will be practiced in the future. Moreover, in the field of oncology, clinical molecular
diagnostics and biomarker discoveries are constantly advancing, with predictive
biomarkers guiding both therapy and monitoring of disease progression or remission
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