1. Personalized medicine aims to provide tailored treatment based on an individual's unique attributes by using diagnostic tools to identify biological markers, often genetic, to help assess which medical treatments will be most effective. 2. Pharmacogenomics plays a key role by studying how genetic variations affect individual responses to drugs to optimize efficacy and minimize adverse reactions. This allows for more targeted therapies and precise dosing. 3. The Human Genome Project mapped the entire human genetic code, opening up possibilities for diagnosing and treating diseases based on a person's genetic profile. Now, molecular testing guides treatment decisions and replaces some invasive procedures.

1. Personalized Medicine
&
Customized Drug Delivery

2. INTRODUCTION
Could I really get a treatment that is made just for me?
Well, not quite, but thanks to the huge advances in our understanding of how both our bodies and diseases work, we can
now develop a much more precise picture of which medicines would be most effective for a particular individual.
Personalized medicine is therefore about providing a far more tailored treatment, one that targets particular attributes that are
unique to you.
We all are similar, of course, but we are also different. And the idea that medicine would be applied in a fashion that
ignores those differences can't be any more correct than going to the shoe store and buying any old pair of shoes without
checking the size.
Personalized medicine is a fantastic opportunity to take a "one size fits all" approach to diagnostics and
drug therapy and prevention and turn it into an individualized approach.
Genomics is playing a big role in the emergence of personalized medicine, because it gives us a window in a very specific
molecular way into those differences between us and allows the opportunity for making individual predictions about disease
risk that can help somebody choose a prevention plan that is right for them.

4. So what exactly is Personalized medicine…
Personalized medicine, sometimes referred to as precision or individualized medicine, is an emerging field of medicine
that uses diagnostic tools to identify specific biological markers, often genetic, to help assess which medical treatments
and procedures will be best for each patient.

5. The example of warfarin:
Warfarin is the FDA approved oral anticoagulant commonly prescribed to patients with blood clots. Due
to warfarin’s significant interindividual variability in pharmacokinetics and pharmacodynamics, its rate of
adverse events is among the highest of all commonly prescribed drugs.
However, with the discovery of polymorphic variants in CYP2C9 and VKORC1 genotypes, two genes that
encode the individual anticoagulant response, physicians can use patients’ gene profile to prescribe optimum
doses of warfarin to prevent side effects such as major bleeding and to allow sooner and better therapeutic
efficacy.

7. History and Evolution of personalized medicine -
Clinicians have for many decades tried to deliver care that is better catered to the individual, such as
understanding that different blood groups require different transfusions. It was the rise of medical genetics in the
latter half of the 20th century following the discovery of the structure of DNA that opened up the possibility of
diagnosing patients through their genetic code.
This culminated in the Human Genome Project – an international program whose goal was the complete
mapping and understanding of all the genes of human beings. It began in the early 1990s and in 2003, the full
sequence of around 20,500 human genes was completed and published.
.

9. Where are we now…
Many diseases, including some type of cancers, are caused by alterations in the genomic make up of a cell –
making the cell cancerous. Genomics can identify these alterations and search for them using an ever-growing
number of genomic tests.
Currently, the Cancer Genome Atlas in the United States has mapped key genomic changes in more than 30
types of cancer. Some of them are driving the cancer (oncogenic driver, some of them are so called “passenger
alterations” which mark a certain disease but are not necessarily the only drivers of it). So, while there is still
long way to go, the more biomarkers we can identify, the greater the potential to deliver more detailed diagnoses
and develop better treatments.
Human beings are 99.9 percent identical in their genetic makeup, differences in that remaining 0.1 percent hold
vital clues about both the causes of diseases and why people can respond differently to different medications.

10. BENEFITS
Personalized medicine benefits patients and the health system by:
1. Shifting the Emphasis in Medicine from Reaction to Prevention
• Women with harmful BRCA1 and BRCA2 mutations also have up to a 39 and 17 percent chance, respectively, of
developing ovarian cancer, compared with a 1.3 percent chance among the general female population. The BRCA1 and
BRCA2 genetic tests can guide preventive measures, such as prophylactic surgery, chemoprevention, and more frequent
mammography.
• Personalized medicine also opens the door to early intervention for patients with familial hypercholesterolemia, which is
characterized by a mutation in the LDL receptor gene. These patients can take drugs that block the PCSK9 gene (known
as PCSK9 inhibitors) to reduce their cholesterol levels and potentially decrease their risk of developing coronary artery
disease.
2. Directing Targeted Therapy and Reducing Trial-and-Error Prescribing
• In many disease areas, diagnostic tests enable physicians to identify the most effective treatment for a patient immediately
by testing for specific molecular characteristics, thus avoiding the frustrating and costly practice of trial-and-error
medicine. One of the most common applications of this practice has been for women with breast cancer.
• Oncotype DX® and MammaPrint®, for example, use prognostic markers to help physicians target the best course of
treatment for breast cancer patients.

11. 3. Reducing Adverse Drug Reactions
In traditional system, dosing was typically adjusted for the individual patient through multiple rounds of trial-and-error,
during which the patient may be at risk. According to several studies, about 5.3 percent of all hospital admissions are
associated with adverse drug reactions (ADRs).
Many ADRs are attributed to variations in genes that code for drug-metabolizing enzymes, such as cytochrome P450
(CYP450). These variants cause drugs to be metabolized either faster or slower than normal. As a result, some individuals
have trouble inactivating a drug and eliminating it from their bodies, leading to systemic overexposure to the drug, while
others eliminate the drug too rapidly before it has had a chance to work. Thus, these genetic variations should be
considered when determining dose.
4. Revealing Additional Targeted Uses for Medicines and Drug Candidates
Molecular testing can also help identify the most appropriate uses for therapies that were initially targeted to the general
population. The lung cancer drug gefitinib (Iressa®), for example, did not demonstrate a survival advantage in a general
population of lung cancer patients in clinical trials, and was withdrawn from the market in 2005 after initially being
granted accelerated approval in 2003. However, continued clinical research revealed benefits in patients who test positive
for epidermal growth factor mutations. FDA approved Iressa® as a first-line treatment for this subset of patients in 2015.

12. 5. Avoiding Invasive Testing Procedures
Molecular tests that simply require a blood sample can also sometimes replace invasive and uncomfortable
tissue biopsies. For example, Allomap®, a multi-gene expression test, detects whether the immune system
of heart transplant recipients is rejecting the new organ.36 Approximately 25 percent of heart transplant
patients experience a rejection, which can prove fatal. To monitor for rejection, heart tissue biopsies are
performed as frequently as once a week after the transplant, and then every few months thereafter for
several years. This invasive procedure requires inserting a tube into a vein in the neck and threading it to the
heart to obtain the biopsy, which is uncomfortable for patients and has risks associated with injury to the
vein and heart. Patients who are monitored for rejection using Allomap have equivalent outcomes as those
who receive heart tissue biopsies, but without the associated risks and complications.

13. BIOMARKERS
A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process,
or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a
disease or condition.

14. TYPES OF BIOMARKERS
• TYPE 0: Natural History Biomarkers
• Measure natural history of disease and correlate over time with known clinical indicators.
Eg. CRP
• TYPE 1: Drug Activity Biomarkers
• Indicate the effect of drug intervention.
Eg. HbA1C
• TYPE 2: Surrogate Markers
• Serve as substitute for a clinical outcome of a disease and also predict effect of a therapeutic intervention.
Eg. Blood pressure is surrogate marker in hypertension.
• Prognostic Biomarkers
• Suggest likely outcome of a disease in untreated individual.
Eg. Prostatic specific antigen to predict survival in prostatic cancer.
• Predictive Biomarkers
• Identify patients likely to respond positively to given treatment.
Eg. HER 2 for Trastuzumab

15. Important characteristics of Biomarkers
According to FDA, an ideal biomarker should be
• specific for a particular disease and able to differentiate between different physiological states
• safe and easy to measure.
• rapid so as to enable faster diagnosis.
• cheap
• able to give accurate results.
• consistent between different ethnic groups and genders.

16. Pharmacogenomics
• What is Pharmacogenomics?
Pharmacogenomics is the study of how genes affect a person’s response to
particular drugs. This relatively new field combines pharmacology (the science of
drugs) and genomics (the study of genes and their functions) to develop effective,
safe medications and doses that are tailored to variations in a person’s genes.
• What is Pharmacogenetics?
Pharmacogenetics is the science that studies how genetic variations in individuals
affect their response to medications.
• It is estimated that genetics can account for 20 to 95 percent of variability in
drug disposition and effects.
• Nongenetic factors include: age, organ function, concomitant therapy, drug
interactions, and the nature of the disease.

17. • One major cause of this difference is that people inherit variations in their genes, and even slight variations can
affect how the body responds to certain medications.
• Pharmacogenetics is the science that studies how genetic variations in individuals affect their response to
medications.
• The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes that are thought
to affect drug response, whereas pharmacogenomic studies encompass the sum of all genes (i.e., the genome).
• However, most currently available drugs are metabolized by the enzymes in the cytochrome P450 (CYP 450)
system. These enzymes, and variations thereof, are responsible for individual variation in absorption, distribution,
metabolism and excretion of drugs. Hence, just a minor variation, such as one nucleotide base “misspelling,” can
have clinically profound consequences.

18. Goals of Pharmacogenomics
Pharmacogenomics aims to
develop rational means to
optimize drug therapy, with
respect to the patients' genotype,
to ensure maximum efficiency
with minimal adverse effects.
Other benefits are by monitoring
biomarkers- reduced time, cost
and failure rates in clinical trials
in developing new medications
and increases opportunities to
develop novel therapeutics
Aids in new drug development

19. Pharmacogenomics- Under the Umbrella of
Personalized Medicine
• Better medication choices
✔ 100,000 Americans die annually and 2,000,000+ are hospitalized due to adverse reactions to medications
✔ Predict individual reactions to drugs
• Safer dosing options
✔ More exact dosing, optimum result/side effect balance
• Improvements in drug development
✔ Exclude genetic variations from certain clinical trials, speeding up drug design time

20. HUMAN GENOME PROJECT(HGP)
• Human genome project was an international scientific research project that aimed to determine the complete
sequence of nucleotide base pairs that make up human DNA and all the genes it contains.
• The idea was picked up in 1984 by the US government and was formally launched in 1990 and completed in 2003.
• The Human Genome Project (HGP) was a 13-year project coordinated by the U.S. Department of Energy (DOE)
and the National Institutes of Health.
• The genome of any given individual is unique ; mapping the human genome involved sequencing the genomes of a
small number of individuals then assembling these together to get a complete sequence of each chromosome.
HGP researchers deciphered the human genome in 3 ways-
• Determining the sequence of all bases in our genome’s DNA
• Making maps that show gene locations of our chromosomes
• Producing linkage maps through which inherited traits can be tracked over generations

21. GOALS OF HGP
• To identify all the approximately 20,500 genes in human DNA,
• To determine the sequences of the 3 billion chemical base pairs that make
up human DNA,
• To store this information in databases,
• To improve tools for data analysis,
• Allow the private sector to have access to the informations and
technologies that arise from this project
• To address the ethical, legal, and social issues (ELSI) that may arise from
the project.
• Improve the sequencing technology by developing new and more effective
methods

22. Advantages of Pharmacogenomics
To predict patients response to a drug
To minimize or eliminate adverse events
To develop customized prescriptions
To improve efficacy and patient compliance
To improve rational drug development
Pharmacogenetic has to be conducted only once during the lifetime
To develop more powerful and safer vaccines
To allow improvements in drug discovery and development

23. Categories of Patients for Personalized Medicine
• Patients are mainly classified depending upon the genetic Polymorphism:
a) Cytochrome P450 genetic polymorphism
b) Different families of enzyme polymorphism
• Focusing on genomics , three categories have been identified;
1. Optimizing drug response: gene-drug interactions:
• A persons genetic constitution can be determined in order to address gene-drug interactions. The aim is to optimize drug
efficacy and to minimize adverse events from drug treatment.
• Applications include genetics-based and genomics based tests that commonly target medicines that are administered to
populations with a specific gene variant.
• In gene-drug interactions, the focus is directed to either metabolism genes or genes related to immune system.

24. 2. Gene based drug targeting:
• Another area of individualization is the development of molecular mechanism specific treatment , also called gene
based drug targeting .
• Most research efforts have been seen in the field of oncology (somatic variations) and great attention has been paid
to genetically based diseases , such as cystic fibrosis as well.
• Apart from this many research efforts are undertaken in disease areas in which there is significant genetic
association with the disease , as in the case with VKORC1 gene in thrombosis patients.
3. Prediction and Diagnosis
• Lastly, individualization efforts are undertaken to;
a) Diagnose more accurately (detailed disease characterization or diagnosis of hereditary diseases that are not well
understood yet)
b) Predict risk of disease
c) These efforts provide greater insight into a patient’s constitution, contributing to a better diagnosis.

25. Pharmacogenetics – A Case Study
• Enzyme called TPMT (thiopurine methyltransferase)
plays an important role in the chemotherapy
treatment of a common childhood leukemia by
breaking down thiopurines.
• A small percentage of Caucasians have genetic
variants that prevent them from producing an active
form of this protein.
• As a result, thiopurines elevate to toxic levels in the
patient because the inactive form of TMPT is unable
to break down the drug.
• Today, doctors can use a genetic test to screen
patients for this deficiency, and the TMPT activity is
monitored to determine appropriate thiopurine
dosage levels

26. • The middle part of the figure provides a short (and incomplete) list of the types of technologies that can be performed. This list includes
types of tests based on demographics, patient history, and a physical examination, all of which have been used for centuries in the
process of differential diagnosis.
• Besides the tests that have been used for a long time, there are some relative newcomers such as advanced imaging technologies (e.g.,
magnetic resonance imaging) and so-called -omics technologies such as genomics. Genomics is of particular significance when it comes
to personalized medicine.
What Kinds of Medical Tests Are Available?

27. • For example, a test often informs treatment decisions that
ultimately make the patient better. The figure, shows a list of
different medical decisions that can be made. To start with, a
clinician can use a test to decide whether or not a patient will
benefit from a particular drug.
• In other cases, a test can help determine whether the patient will
be more likely to have a serious adverse event after being given a
drug. An example of such a test can be found in patients with
epilepsy and other indications for carbamazepine. Patients with
HLA-B*1502 are more likely than other patients to have
dangerous skin reactions following carbamazepine therapy.
• Sometimes the question at hand is not about which drug to use,
but rather about which dose to use.
• Many other treatment decisions, however, involve not only drugs
but also other options such as surgery, radiotherapy, and
watchful waiting.
What Kinds of Medical Decisions Might Be Involved in Personalized Medicine?

28. Personalized Medicines and It’s Challenges
• Insufficient Understanding of Internal Biology of Disease: This field is not known to all, people are not much aware
about the concept of personalized medicine.
• Limited Infrastructure: It is main aspect that should be consider during the preparation of personalized medicine, the
requirement of accessories or computerized during the gene detection or manipulation need more time as well as
money also.
• Limited drug alternatives : Only one or two approved drugs may be available for treatment of a particular condition.
If patients have gene variations that prevent them using these drugs, they may be left without any alternatives for
treatment
• Accessibility of Personalized Medicine to the Patients
• Complexity of finding gene variations that affect drug response: limited knowledge of which genes are involved
with each drug response. Since many genes are likely to influence responses, obtaining the big picture on the impact
of gene variations is highly time-consuming and complicated

29. Personalized Medicines in Market Till Now…
Trade name of drug Class of drug Generic name of drug Target site
Tarceva
Iressa
Tagrisso
Tyrosine kinase inhibitor Erlotinib
Gefitinib
Osimertinib
Epidermal growth factor
receptor
Portrazza
Avastin
Cyramza
Monoclonal antibody Necitumumab Vascular endothelial
growth factor receptor

30. Approved personalized drugs….

31. Clinically Available Pharmacogenomic Test

32. METHODOLOGY

33. AmpliChip
• The Amplichip CYP450 test is first FDA approved pharmacogenetic test on
Dec 24, 2004
• The AmpliChip CYP450 Test uses micro array technology
from Affymetrix (Gene Chip) to determine the genotype of the patient in terms
of two cytochrome P450 enzymes: 2D6 and 2C19.
• The test aims to find the specific gene types (a genotype) of the patient that
will determine how he or she metabolizes certain medicines, therefore guides
the doctors to prescribe medicine for best effectiveness and least side effects.
• The DNA sample comes from blood or, alternatively, comes from a mouth
brush called buccal swab. The analysis has five steps after DNA is extracted
from patient samples:
1. PCR amplification of the gene.
2. Fragmentation and labeling of the PCR product
3. Hybridization and staining on the AmpliChip DNA microarray.
4. Scanning the chip.
5. Data analysis.
The main criticism of the test is that the test finds out the genotype (the makeup
of the gene types) of the patient, which does not necessarily cover all the
phenotypes (the actual biological effect). For example, some argue that the so-
called ultra-rapid metabolizer, who has extra copies of the 2D6 gene expressed,
cannot be reliably tested.

34. Applications of Personalized Medicine…
Cystic Fibrosis
• Cystic fibrosis is a serious genetic disorder caused by mutations in a gene that
encodes for a protein called CFTR, which regulates the absorption and secretion of
salt and water in the body.
• Ivacaftor targets the defective CFTR protein in patients that have one of several,
resulting in significant and sustained improvement in lung function.
• Kalydeco is the first available treatment that targets the defective CFTR protein,
which is the underlying cause of cystic fibrosis. This is a breakthrough therapy for
the cystic fibrosis community because current therapies only treat the symptoms of
this genetic disease.

35. Metastatic Colorectal Cancer
• In recent years, scientists have identified the molecular receptor
on colorectal cancer cells that causes them to multiply (epidermal
growth factor receptor, or EGFR)
• New medicines that target these receptors are improving survival
outcomes.
• Cetuximab, a type of targeted monoclonal antibody therapy,
blocks the signals from EGFR.
• Continuing research revealed that the presence of a specific
mutation in a particular gene (KRAS) is associated with
resistance to cetuximab.
• Testing for the KRAS gene allows for better targeting of therapy
and improved patient survival.

36. STATUS IN INDIA
⮚ In India, PM is still at an early adoption stage but is a rapidly advancing field of
healthcare.
⮚ Some start-ups are fueling PM and diagnostics:
• Molecular diagnostic tests developed by Abbott® India can identify which cancer
patients will respond to certain medicines.
• Also received approval for the first US FDA-approved hepatitis C genotyping test
which can identify the specific type of HCV strain present in the blood of the
infected individual.
• Positive Bioscience® has partnered with Medanta®-The Medicity to launch India’s
first personal genomics clinic.
• Xcode Lifesciences® has come up with lnDNA technology to provide s
solutions to lifestyle-related diseases such as diabetes. .
✔ DNA extracted from saliva can then be used to determine the allelic
information of the individual using high-throughput genotyping
techniques.
• NutraGene® launched the country’s first commercial genetic test for type 2
diabetes.