133reduction in adverse drug reactions, improved outcome and cost-effectiveness.
There are two approaches to application of pharmacogenetics for determining drug
response profi les: candidate gene approach and SNP profi le approach.
Candidate Gene Approach This approach involves generation of specifi c hypoth-
eses about genes that cause variations in drug responses, which are then tested in
responders and non-responders. Candidate drugs that are selectively metabolized by
polymorphic enzymes can be dropped early in drug screening. Thus there will be
fewer dropouts from late-stage clinical trials. Based on the results of clinical trials,
pharmacogenetic genotyping can be introduced into routine clinical practice.
SNP Profi le Approach This involves search for SNP profi les that correspond to
effi cacy or adverse events in suitable populations. It will be possible, over the next
few years, to use advances in SNP mapping technology to correlate information
from patients’ DNA with their response to medicines. This provides signifi cant
opportunities to enhance current drug surveillance systems by collecting data that
would enable rare serious adverse events to be predicted in subsequent patients
before the medicine is prescribed.
An important challenge in defi ning pharmacogenetic traits is the need for well-
characterized patients who have been uniformly treated and systematically evalu-
ated to make it possible to quantitate drug response objectively. Therefore, it should
be the routine to obtain genomic DNA from all patients enrolled in clinical drug
trials, along with appropriate consent to permit pharmacogenetic studies. Because
of marked population heterogeneity, a specifi c genotype may be important in deter-
mining the effects of a medication for one population or disease but not for another;
therefore, pharmacogenomic relations must be validated for each therapeutic indi-
cation and in different racial and ethnic groups.
Postmarketing Pharmacogenetics
An example of application of pharmacogenetics in post-marketing phase of Abacavir
(GlaxoSmithKline), which is commonly applied in a triple therapy against
HIV. Between 3 % and 5 % of the patients are hypersensitive to abacavir and have
risk of various reactions including anaphylactic shock. The company is aiming to
design a test, which would help the physicians to decide which patients can receive
it safely. A retrospective case-control study is being conducted in two phases all
subjects identifi ed from GlaxoSmithKline studies. The fi rst phase includes a study
of candidate genes: 114 markers including HLA-A, -B and -DR. The second phase
includes whole genome SNP analysis. The goal of the study is 100 cases and 200
controls matched in 1:2 ratio. This will enable detection of a difference in frequency
of 15–20 % with 80 % power. Results from various projects of GlaxoSmithKline
suggest that association studies can be applied successfully to pharmacogenetics
and the company is committed to the use of SNPs throughout the drug discovery
process.
Role of Pharmacogenetics in Pharmaceutical Industry