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Drugs get a human face
In the not-too-distant future, our genes will determine
the type of drug and its dosage.Pharmacogenomics offers the promise
of tailor-made drugs and gives a way into the therapy that targets
specific ailments.Katya Naidu explores the finer aspects
of this new form of therapy.
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drug does not have the same effect on every individual. Genetics
decide the rate and extent of drug absorption, distribution, metabolism
and excretion, in other words how much of the drug is available
to an individual and for how long. Since a drug reaction in an individual
is specific and unique, a doctor faces a plethora of issues while
prescribing a drug given the danger of adverse drug reactions.
“About two to three percent of hospitalisations are due
to adverse drug reactions. In certain patients the adverse drug reactions can
be far beyond the extreme stages,” says Dr Hemant P Thacker, Honorary Physician
at Jaslok Hospital.
The answer to the predicament lies in pharmacogenomics, which
holds the promise that drugs might one day be tailor-made for individuals and
adapted to each person's genetic make-up. “We have known for ages that
drugs are not equally effective in individuals. It was even known there must
be a genetic basis for such variability. Genomics gave us valuable tools to
decipher the variations in the gene-enzyme make-up of an individual. This combination
has resulted in the concept of pharmacogenomics which is an extension of the
concept of pharmaco- genetics,” says Prof Harish Padh, Director of BV Patel
Pharmaceutical Education and Research Development (PERD) Centre.
| Personalised medicine drastically reduces
the time and costs for therapy vis-à-vis the trial-and-error method.
In addition, it also reduces the background research done by most doctors
before prescribing a drug. Says Dr Hemant Thacker, “For either the
uneducated patients who cannot express, who do not remember, who do not
tell or cannot construe or for the lazy physician who has not fulfilled
his role properly, if you are using genomics you are targeting that organ,
so you are saving the others.”
Multi-drug reactions is yet another issue that doctors
come across while dealing with patients of multiple disorders. “Different
specialists prescribe different medicines. If everyone uses a combination
of medication, the marriage just doesn't work.” Targeted therapy
solves this problem too as it is designed to hit the right site and avoids
unwanted side-effects.
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Dr Hemant P Thacker
Honorary Physician
Jaslok Hospital
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The redemption
As no two fingers of the palm are the same, the genetic make-up of each
individual is unique. Pharmacogenomics is atte-mpting to identify genotypes
and make tailor-made drugs that hit the right target.
The genetic level story of drug disposition is very simple. The human genome
has about 20-30 genes for specific genotypes, which are responsible for drug
disposition.
These genes, also called loci, determine how a person responds
to a therapeutic agent. Variations of these genetic loci ascertain whether one
benefits from a given therapy or one is likely to suffer an adverse drug reaction
or toxicity. Understanding alleles at these loci helps decide the right type
of drug and right dose for the individual, depending on the polymorphism of
the gene. And this understanding gives way to pharmacogenomics, which aims at
differentiating population by genotyping.
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Allele: is an alternative form of a genetic locus; a single allele
for each locus is inherited separately from each parent
Apoptosis is a type of cell death in which a series of molecular
steps in a cell leads to its death
Biomarker: A specific physical trait used
to measure or indicate the effects or progress of a disease or condition
Chromosome: A threadlike linear strand of
DNA and associated proteins in the nucleus of eukaryotic cells
that carries the genes and functions in the transmission of hereditary
information
DNA: A nucleic acid that carries the genetic
information in the cell and is capable of self-replication
Gene: A hereditary unit consisting of a sequence
of DNA that occupies a specific location on a chromosome and determines
a particular characteristic in an organism. Genes undergo mutation when
their DNA sequence changes.
Genome: The total genetic content contained
in a haploid set of chromosomes in eukaryotes, in a single chromosome
in bacteria, or in the DNA or RNA of viruses
Loci: is the position on a chromosome of
a gene or other chromosome marker; also, the DNA at that position. The
use of locus is sometimes restricted to mean regions of DNA that are expressed.
The specific physical location of a gene on a chromosome
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The genotypes
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Prof Harish Padh
Director
PERD Centre
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According to Padh, genotyping methods classify individuals
into four classes for a given group of drugs: poor metabolisers (PMs), intermediate
metabolisers (IMs), extensive metabolisers (EMs) and ultra rapid metabolisers
(UMs). The PM subjects develop higher serum drug concentrations in comparison
with EMs, resulting in increased risk of suffering from concentration-dependent
side effects when subjected to standard recommended doses. On the other hand,
UM subjects do not reach therapeutic serum concentration upon treatment with
standard doses. They may fail to respond to treatment.
Moreover when the parent compound is a pro-drug, which requires bio-activation
by the enzyme, the effects of polymorphism can be quite complex in PMs and UMs.
Identification of PM and UM subjects can be useful in drug selection and dosage
could be tailored to the individual patient from the beginning, which can help
avoid adverse reaction or therapeutic failure. Recognising different targeted
groups can initiate therapy that is effective in these target groups.
However, genotyping will depend upon the polymorphism of the gene. It will not
be same for all the diseases and drugs but will be the same for a number of
drugs metabolised by the same enzyme. PERD Centre is in the process of genotyping
the individuals for various cytochromes responsible for metabolism of commonly
used drugs such as b-adrenoceptor blockers, anti-depressants, neuroleptics,
anti-arrhythmic (cytochrome 2D6); macrolide antibiotics, HMG CoA reductase inhibitors,
steroid 6b-OH (cytochrome 3A4); proton pump inhibitors, anti-epileptics (cytochrome
2C19).
Targeting cancer
Pharmacogenomics aid drug delivery systems in difficult diseases like cancer.
Considering the significant heterogeneity associated with responses to chemotherapeutic
agents and their narrow therapeutic indices, pharmacogenomics has the potential
to offer individualised cancer treatment regimens. A better understanding of
genetic determinants of chemotherapeutic response will enable the identification
of patients who are at the risk of an adverse reaction.
Research in advanced targeted drug delivery systems for cancer
therapy that is underway at the Department of Pharma-ceutics, Rutgers, The State
University of New Jersey, aims at developing a novel four-drug component targeted
pro-apoptotic drug delivery system. The study aims to design a drug delivery
system which will increase the efficacy of the cancer treatment by targeting
the anti-cancer drug specifically to cancer cells, simultaneously inducing programmed
cell death and the suppression of main anti-apoptotic cellular defence mechanisms.
| In spite of all the benefits that pharmacogenomics
promises, there are quite a few roadblocks that will be encountered while
implementing pharmacogenomics:
Complexity: The complexity of a subject like
genetics and the limited knowledge of genes make the process of pharmacogenomics
elaborate
Limited alternatives: The system of medicine
has limited options for a patient with a particular condition. If gene
variations rule out a drug used by a patient, it will further decrease
the options of treatment
Educating doctors: Multiple products to treat
the same condition for different population subsets will complicate the
process of prescribing drugs. Physicians require a better understanding
of genetics and must be trained and educated accordingly
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One for all!
While targeted therapy can solve a number of problems on the healthcare front,
it might create a fresh set of troubles for pharma companies who have been following
the one-size-fits-all theory for years. Classifying the patient population will
reduce the target market and will dilute the chances of blockbuster drugs which
pharma companies thrive on.
Padh says, “I partly agree as this will be true in the cases where the
drug is not effective because of some particular type of genotype and another
drug has to be given for the treatment. Segmented patient population will not
be liked by pharma companies. However, there will be many factors because of
which companies will save on the cost of drug development, for example, fewer
patients of right genotype in clinical trials.”
Vinod Mattoo, Medical Director of Eli Lilly, while saying that the company is
working on cancer related pharmacogenomics, downp-lays the blockbuster scare.
He says, “It is in the interests of the patients, companies and physicians
to deliver niche drugs that will be effective.” Companies with extended
vision like Eli Lilly have already made strides into research in this area.
“Lilly is conducting investigational studies for developing biomarkers
in the area of targeted therapy, especially in oncology,” informs Mattoo.
editorial@expresspharmaonline.com
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