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predominantly white subjects in the US, and demonstrated 100% sensitivity of the HLA-B*5701
allele for ABC-induced hypersensitivity in white and black subjects [76] . These studies pro-
vided strong evidence for the clinical utility of HLA-B*5701 to prevent ABC HSR, generalizable
across race. Another important aspect of the PREDICT-1 study was that 45% of HLA-B*5701
carriers were able to tolerate ABC. The study of ABC-exposed HLA-B*5701-positive subjects
holds the key to understanding the additional factors required for the development of the syn-
drome in hypersensitive patients or, conversely, the protective factors in tolerant patients. These
efforts, together with the availability of a test to screen for HLA-B*5701 culminated in the fol-
lowing FDA warning in the package insert for abacavir:
'Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to
abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this
approach has been found to decrease the risk of hypersensitivity reaction. Screening is also recommended
prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated
abacavir. HLA-B*5701-negative patients may develop a suspected hypersensitivity reaction to abacavir;
however, this occurs significantly less frequently than in HLA-B*5701-positive patients.' [77] .
This example underscores the many hurdles, not least of which is prospective testing of
a candidate patient selection / exclusion tool, that need to be overcome before an exciting
genomic result can be translated into clinical practice to aid patients.
1.4.2 PPARgamma Agonists in Type II Diabetes
We turn now to a translational approach that employed identifying risk factors as above
but then applied the knowledge pre-clinically to a drug discovery effort to identify new pipe-
line molecules with reduced liability of causing the ADR associated with the lead compound.
Peroxisome-proliferator activated receptor (PPAR) agonists that activate the transcription
factor PPARgamma have been approved to control glycemia in Type II diabetics [78] . These
agents are frequently associated with edema or fluid retention and less commonly congestive
heart failure [78] . Muraglitazar was an investigational drug that activated both PPARalpha
and PPARgamma transcription factors. In Phase II clinical trials it showed robust efficacy with
regard to lowering blood glucose levels and was associated with dose-dependent edema [79] .
By comparing subjects who developed edema to those that did not, Geese and colleagues
identified renin, endothelin-1 and the beta-adrenergic receptor as potential susceptibility
genes for muraglitazar-induced edema [80] . In follow up gene expression analysis in a cell-
culture model, it was found that renin and endothelin-1 were significantly induced by mura-
glitazar and all other known PPAR agonists. Remarkably, there was a correlation between the
potency of a PPAR agonist to induce expression of these genes in the cell-culture model and
its propensity to cause edema in humans. The authors applied this knowledge to three other
PPAR alpha / gamma agonists that were indistinguishable in their ability to reduce blood glu-
cose levels in an animal model to predict one candidate drug that would be less likely to cause
edema. Consistent with this prediction, it was found that among the three candidate drugs the
least potent molecule with regard to inducing expression of renin and endothelin was also the
one least likely to cause edema in a non-human primate model. This example is a powerful
illustration of how careful analysis of even early clinical trials can translate to knowledge that
can be applied to improve the discovery pipeline .
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