DOSAGE FORM FOR PERSONALIZED MEDICINE

INTRODUCTION
 In human beings 99.9% bases are same in genes remaining 0.1% persons makes
an unique
 Different attributes (characteristics)
 How a person looks
 Diseases he/she develops

 These variations can be:

 Harmless (change in the phenotype) phenotype is a term refers to
observable physical properties of an organism appearance,
development and behavior.
 Harmful ( diabetes, cancer, heart disease, heamophilia)
 Latent (variations found in coding and regulatory regions are not
harmful, but the change in each gene only becomes apparent under
the certain conditions) eg: susceptibility of lung cancer.

HISTORY
 The concept of personalized medicine dates back many hundreds of years.
 Developments in chemistry, histochemistry and microscopy allowed scientists to
begin to understand the underlying causes of disease.
 Sequencing of the human genome at the turn of the 21st century set in motion the
transformation of personalized medicine from an idea to practice.
 The term personalized medicine first appeared and published in 1999, however
some of the fields core concept have been existence since the early 1960s.
 The advent of new technologies has now made personalized medicine a more
tangible reality and has enabled researches to provide a link between an
individual molecular and clinical practice.
 DEFINITION

 Personalized medicine refers to tailoring of medical treatment to the

individual characteristics of each patient to classify individuals to sub
populations that differ in their susceptibility to a particular disorder or
their response to a specific treatment.
 The ability to offer :
 The right drug
 To the right patient
 For the right disease
 At the right time
 With the right dose
 The other terms used are precision medicine, stratified medicine, targeted
medicine and pharmacogenomic medicine.

BENEFITS OF PERSONALIZED MEDICINE

 Diagnose the disease more accurately
 Increase safety and reduce adverse drug reactions
 Select optimal therapies and target medicines and dosage more precisely
 Detect onset of disease at the earliest moments
 Increase the efficacy of health system by improving quality and
accessibility
 Treatment decision will be improved by patient education
 Some person have similar symptoms but different illness that time
personalized medicines are useful
 Medical interventions may work in some people but not in others
 To avoid any allergic and adverse effects
 Genomics helps to treat the patient effectively and precisely
EXAMPLES OF PERSONALIZED MEDICINE

1.Abacavir
 A nucleotide reverse transcriptase inhibitor used to treat patients
with HIV.
 Its main side effect is hypersensitivity reaction
 The incidence of hypersensitivity reaction is associated with
ethnicity among patients exposed to abacavir, retrospective and
prospective studies show a significantly increased risk of abacavir
induced hypersensitivity reaction in human leukocyte antigen.
 Abacavir interacts specifically with HLA changes the binding
specificity between HLA molecule and HLA presented in
endogenous peptide leading to systemic autoimmune reaction.
 The study of abacavir induced HSR and implementation of HLA is
the successful example of personalized medicine.
2.Warfarin
 It is the most commonly prescribed oral anticoagulant for the
treatment and prevention of thromboembolic events.

3. Cetuximab used in treatment of colon cancer.

 PHARMACOGENETICS
 The word pharmacogenetics is derived from the Greek word
Pharmacon means drug and Genetics means generative.
 Pharmacogenetics: The effect of genetic variation on drug response
including disposition, safety, tolerability and efficacy. It is the study
of how genetic difference in single gene influences the variability in
drug responses.
 Pharmacogenomics: Surveying the entire genome to assess
multigenic determinants of drug response. It is the study of how
multiple genes influence the variability in drug response.
INTRODUCTION
 The term pharmacogenetics was coined by Vogel in 1959.
 Primaquine induced heamolysis in patients with G6PD (Glucose-6-
Phosphate Dehydrogenase) deficiency was the first pharmacogenetic
discovery.
 Currently there are over 120 drugs including vorticonazole, warfarin,
carbamazepine, atomoxetine, azathioprine, irinotecan and cetuximab
who’s labeling includes pharmacogenetic discoveries.
 The FDA published a guidance document to facilitate the use of
pharmacogenetic discoveries in drug development.
TYPES OF GENETIC VARIANTS
 Two major types of sequence variation are:
 Single nucleotide polymorphism (SNPs) :
A Single Nucleotide Polymorphism is a variation in a single
nucleotide that occurs at a specific position in the genome, where each
variation is present to some appreciable degree within a population (eg
>1%)

 Insertions or deletions :
Deletions are less frequent and are low in frequency.
TYPES OF SNP’s
 SNPs usually occur in non-coding regions more frequently
than in the coding regions.

Examples of genetic variation:

Precipitation of porphyra by barbiturates
Haemolysis due to G6PD deficiency
Insulin resistance due to receptor mutations

HOW DOES GENETIC VARIATION AFFECT THE DRUG

PHARMACOKINETICS:

Absorption usually refers to how a drug enters the bloodstream after a person
takes a pill or uses an inhalant, intravenous injection circumvents absorption by putting
a drug directly into the blood.

Distribution describes where the drug travels after absorption and how much of
the drug reaches the target site. Many drugs, for example cannot get pass the blood
brain barrier.

Metabolism refers to how the drugs gets broken down in the body, which can
happen immediately by way of enzyme action in the stomach and sometimes involves
end products with their own pharmacological action.

Excretion describes how drugs leave the body whether by urine, bile or in some
cases exhalation.

PHARMACODYNAMICS:

Pharmacodynamics is the molecular action of a drug on its target, whether this is a

cell surface target of both beta agonists in the treatment of asthma and beta blockers in
the treatment of hypertension and this receptor has polymorphisms that have been
associated with response to these drugs.

DIVISIONS OF PHARMACOGENETICS

 The pharmacokinetics of a drug can be altered by sequence variations in

drug disposition genes.
 The pharmacodynamics of a drug can be changed by sequence variations
in drug target genes.

Drug disposition pharmacogenetics:

 A drug disposition includes absorption, distribution, metabolism and excretion.

 The plasma concentrations of the parent drug or its active metabolites may be
affected by a genetic polymorphism altering the function of a protein that is
involved in the disposition of a drug.
  For example, if a genetic polymorphism leads to lower activity of a metabolizing
enzyme, the plasma concentrations of the parent drug may increase and plasma
concentrations of the metabolites may decrease.

 Examples :

 Warfarin and CYP2C9 polymorphisms

 Tamoxifen and CYP2D6 polymorphisms

 Thiopurine drugs and thiopurine s methyltranferase (TPMT) polymorphisms

Warfarin and CYP2C9 polymorphisms :

 Warfarin reduces blood’s ability to clot and prevents blood clots in vein, arteries
and heart.

 CYP2C9*2 allele results in a 30-40% reduction in enzymatic activity for s-

warfarin metabolism.

 While CYP2C9*3 allele causes an almost complete loss of s-warfarin

metabolism.

 A study in Caucasians found that patients carrying either CYP2C9*2 or

CYP2C9*3 required significantly lower daily dosages of warfarin to maintain a
therapeutic INR compared with patients carrying CYP2C9*1.

Tamoxifen and CYP2D6 polymorphisms :

 Tamoxifen is commonly used for breast cancer treatment.

 CYP2D6 is involved in generating endoxifen from tamoxifen.

 CYP2D6 genotype and phenotype have been associated with variability in

plasma concentrations of endoxifen among individuals.

 The CYP2D6 phenotype traditionally classified as

Ultra extensive metabolizer

Extensive metaboliser
 Intermediate metaboliser

Poor metaboliser

 Extensive or ultra extensive metabolizes would have significantly higher serum

concentrations of endoxifen compared with intermediate and poor metabolizers.

Thiopurines and Thiopurine S-Methyl transferase polymorphisms :

 TPMT metabolizes thiopurine drugs such as mercaptopurine and azathioprine.

 Reduced TPMT activity is associated with a higher frequency of mercaptopurine

associated adverse events such as neutropenia.

 Patients who do not carry TPMT*1 have extremely low TPMT enzyme activity
and almost always develop neutropenia compared with patients with TPMT*1.

 FDA has recommended that clinicians consider a reduction in the dosage of a

thiopurine in patients carrying a non functional TPMT allele.

Drug target pharmacogenetics :

 Pharmacological effects of drugs are exerted by modulating activities of

enzymes or receptors.

 Fewer genetic polymorphisms in pharmacodynamic genes have been recognized

by FDA including:

 Vitamin K epoxide reductase complex subunit 1 gene polymorphisms

(VKORC1) and warfarin response

 Beta 1 adrenergic receptor gene polymorphisms (ADRB1) and beta- blocker

response

VKORC1 and warfarin response:

 VKORC1 encodes vitamin K epoxide reductase which is inhibited by warfarin.

 This inhibition interferes with carboxylation of vitamin K dependent coagulation

factors II, VII, IX, and X.
  Two haplotypes A and B forms by five noncoding VKORC1 SNPs in strong
linkage equilibrium.

 Patients with A haplotype may produce smaller amounts of VKORC1 than do

patients with B haplotype.

ADRB1 and beta-blocker response :

 Ser49Gly and Arg389Gly are the two common SNPs in ADRB1.

 It is hypothesized that hypertensive patients carrying Ser49 or Arg389 would

have greater reduction in blood pressure with beta-blocker therapy.

 Several studies have found that hypertensive patients with Ser49Arg389

haplotype had the greatest reduction in blood pressure with oral metoprolol.

PHARMACOGENETIC STUDIES

Candidate gene studies :

 In patients who have a better drug response, the candidate gene approach tests
how frequent an allele or a set of allele.

 Genes are selected based on their known physiological or pharmacologic effect

on disease or drug response.

 It is a useful tool to study a genetic association with drug response if there is a

plausible link between the gene and the drug response.

 The candidate gene approach is less expensive and requires a smaller sample
size than GWAS.

 A major disadvantage is that it requires prior knowledge of the function of the

gene regarding the drug response.

Genomic Wide Association Study (GWAS) :

 The role of common genetic variations in disease or drug response surveyed by

GWAS.

 GWAS was done by genotyping in large sets of SNPs across the genome.
 Most GWASs have been conducted as a case control, cohort or family study.

 GWAS is a great tool to discover new functions of a gene or to identify a new

genetic biomarker used to evaluate drug response.

 It can be used to identify the new biomarkers that could explain the underlying
mechanisms of adverse drug reactions.

 It helps to understand the complex disease development and identify the factors
that affect variable drug responses.

ROLE OF PHARMACOGENETICS IN PHARMACEUTICAL INDUSTRY

 Pharmacogenetics has a threefold role in the pharmaceutical industry including:

 Studying drug metabolism and pharmacological effects

 Predicting genetically determined adverse reactions

 Drug discovery and development and as an aid to planning clinical trials

ROLE OF PHARMACISTS

 Pharmacists may play a key role in applying pharmacogenetic discoveries to

patient care.

 Pharmacists can take a lead in application of pharmacogenetics in clinical

practice since they are experts in pharmacokinetics and pharmacodynamics.

 Pharmacists responsibilities for pharmacogenetics include:

 Promoting the optimal use and timing of pharmacogenomic tests

 Interpreting clinical pharmacogenomic test results

 Educating other pharmacists, fellow health care professionals, patients and the
public about the field of pharmacogenomics.

LIMITATIONS OF PHARMACOGENOMICS

 The drug response is probably affected by multiple genes.

  Drug response might be predicted from a certain pattern of polymorphisms
rather than only a single polymorphism.

 Holding sensitive information on someone’s genetic makeup raises questions of

privacy and security and ethical dilemmas in disease prognosis and treatment
choices.

Applications of Pharmacogenomics
 Improved drug safety and reduced ADR’s
 Tailor treatment to meet patient’s unique gene (predisposition, identifying,
optimal closing)
 Improve drug discovery targeted to human diseases
 Improve proof of principle for efficacy trials
 Pharmacogenomics are applied in many areas like pain management, cardiology,
oncology, psychiatry, forensic