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SUMMARY
Variation in drug response can result in therapy failure or adverse drug
reactions (ADRs). The clinical consequences range from mild, self-limiting
side effects to serious illness or death. In the UK and the rest of Europe,
data have shown that around 7 per cent of hospital admissions are caused
by ADRs.
In the US, ADRs occurring in hospital rank among the top six
causes of death.
Genetic factors are estimated to account for 20 to 95 per cent of interpatient
variability.
Unlike other factors that influence drug response, inherited
determinants that affect drug metabolising enzymes, drug receptors and
drug transporters, remain stable throughout a patient’s life. The story so far
The term “pharmacogenetics” was first used in the 1950s to
describe clinical observations of inherited differences in drug effects.
It now describes the study of how interindividual variations in DNA sequence
are related to drug response. The use of genetic markers in healthcare
is not a new phenomenon, but has been used for years (eg, in organ transplant
and blood transfusions).
The completion of the Human Genome Project (HGP) is one of the greatest
scientific achievements of the past 50 years. This project, which was completed
in 2003, identified the thousands of protein-coding genes in the human
genome and sequenced the billions of chemical base pairs that make up human
DNA.
An explanation of the basic terms used in pharmacogenetics can be found
in Panel 1. Genetic make-up is broadly similar
in humans, regardless of gender or ethnicity. However there are small variations
in the genetic
code, referred to as single nucleotide polymorphisms (SNPs) (see p160),
which can have a profound effect on how an individual develops disease
or responds to a medicine.
The HGP identified over 1.4 million SNPs, with at least 60,000 of them
in the coding regions of genes. Research in
pharmacogenetics has gained momentum in recent years, fuelled by these
findings. It is hoped that increased knowledge in this field will allow
genetic information to be used to inform prescribing decisions and allow
more accurate prediction of drug safety and efficacy in individual patients.
However, despite it being over 50 years since the conception of pharmacogenetics,
most clinicians still prescribe on a “one drug fits all” basis.4
The potential in this field is yet to be realised, but there are several
current examples of how pharmacogenetic testing is improving patient care.
The second
part of this feature (p167) discusses these examples.
Some of the terms used by the pharmacogenetics industry are defined in
Panel 2. The application of pharmacogenetics
falls broadly into two groups:
• Using genetic information to test for variation in an individual’s
germline DNA (the inherited genetic make-up of every cell in the body),
which may, for example, determine the activity of a drug metabolising enzyme
• Analysing the DNA of tumour cells (this may be different from cells in
the rest of the body and not inherited)
Panel 1: A refresher in pharmacogenetics
A gene is a strand of DNA, in which nucleotides are
contained in coding regions and non-coding regions. The sequence
of nucleotides in a coding region denotes the amino acid sequence
of a protein that is required for the cell to function. The sequence
of nucleotides in a non-coding region may have little or no known
function.
Occasionally, one of the nucleotides in a DNA sequence may change.
This is known as a single nucleotide polymorphism (SNP). If the SNP
occurs in the coding region, this can lead to an alteration in the
amino acid sequence of the encoded protein and, potentially, a protein
with altered function. This can affect pharmacodynamic or pharmacokinetic
processes.
All genes exist in two places in the body: at the same location on
two homologous chromosomes. The two forms of the gene are known as
alleles. If the two alleles are identical, the person is homozygous
for that gene. If the two alleles differ, the person is heterozygous
for that gene.
Organisms can be classified in two ways:
• By genotype — according
to a genetic characteristic (eg, possesses the human
leucocyte antigen B*5701)
• By phenotype — according to a biological characteristic (eg,
a poor metaboliser of a particular drug) that can be the result of
genetic or environmental factors |
Panel 2: Definitions of terms used
in the pharmacogenetic industry
The terms “pharmacogenetics” and “pharmacogenomics” are
often interchanged and used collectively to refer to targeting medicines
on the basis of genetic data. The data can provide information about
an individual’s ability to absorb, distribute, metabolise or
excrete a medicine. Alternatively, it may indicate the susceptibility
of a tumour or virus to a particular medicine.
The European Agency for the Evaluation of Medicinal Products offers
the following definitions:
• Pharmacogenetics — the study of interindividual
variations in DNA sequence
related to drug response
• Pharmacogenomics — the study of the variability of the expression
of individual genes relevant to disease susceptibility as well as
drug response at cellular, tissue,
individual or population level (the term is broadly applicable to
drug design,
discovery and clinical development)
A pharmacogenetic test has been defined by the
Nuffield Council on Bioethics as “a test to detect the presence or absence of,
or change in, a particular gene or chromosome in order to predict
a person’s response to a medicine”. The test can be done
directly (by analysing a person’s DNA) or indirectly, by examining
DNA products, such as proteins. |
Panel 3: Factors that will influence
the uptake of
pharmacogenetic testing
Medical need A test that has the potential to prevent
a drug from causing a life-threatening side effect will be more valuable
than one that prevents a mild, self-limiting side effect. In addition,
if a drug is expensive, a test that predicts its effectiveness has
the potential to increase the benefit to the overall patient population
by preventing the drug from being given to a patient who will not
respond.
Potential for improvement A test will be more
useful if it identifies a genetic variance that significantly,
rather than marginally, affects
a patient’s response to a drug. For example, testing for the
presence of HER2 can significantly improve the outcome of trastuzumab
treatment. Understanding the relevance of pharmacogenetic testing
is crucial for those who perform the tests and interpret the results.
Clinical validity Pharmacogenetic tests only provide
predictive information, so will be most effective when they have
a low probability
of false positive and false negative results. Some tests that have
entered clinical practice carry a risk of such results. For example,
HLA B*5701 genotyping does not guarantee whether or not a patient
will be hypersensitive to abacavir.
Some patients can tolerate the
drug despite possessing this variant, whereas others who do not
possess the variant can develop a reaction. Ease
of use Pharmacogenetic tests will need to be rapid and easily
interpretable to be of maximum benefit. |
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Hospital
Pharmacist
