Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

82 Applying Pharmacogenomics in Therapeutics
Another advantage is that these models can also be used to assess the impact of
polymorphisms on druggability. For example, QSAR has been used to develop functional
screening analyses that evaluate the impact of polymorphisms on ABC transporter
function and druggability. 46 Once lead drug candidates have been identified
via in silico studies, druggability is then confirmed via protein binding analyses
(NMR analysis 47 or Biacore; 48 www.biacore.com) and/or enzyme activity assays. 49
An alternative approach to identifying drug candidates for a particular target is the
use of screening assays. Such studies involve the use of panels of existing drugs,
including orphan drugs, and are used to establish the strength of binding between
the drugs included in the panel and the target, or to assess the impact of the drug
on enzyme activity. 50 Again, polymorphic target variant should be included in these
analyses, particularly if the variant is known to have high frequency in the patient
population and/or more potent effects on the disease process.
It is noteworthy that in silico and genomic analyses have led to the realization
that several seemingly different diseases share common underlying genetic causes,
and can in fact be treated with the same drugs. As a result, several drugs have been
successfully “repurposed”: that is, used for an indication that is different from that
they were initially approved for. For example, genomic analyses identified significant
similarities between catechol-O-methyltransferase (COMT), a molecule that
mediates Parkinson disease; and enoyl-acyl carrier protein reductase, a bacterial protein
in Mycobacterium tuberculosis. Genetic alterations in these molecules cause the
associated disease in both instances. As the molecules are so similar, investigators
decided to determine whether entacapone, a drug used to target COMT in patients
with Parkinson disease, would be effective for the treatment of M. tuberculosis; entacapone
is now used to successfully treat tuberculosis. 51 Another example is bexarotene,
a drug that was originally developed to treat cutaneous T-cell lymphoma.
Analysis of signaling pathways led to the discovery that bexarotene can modulate
pathways that drive Alzheimer disease. Studies in mouse models of Alzheimer disease
have shown bexarotene to be effective, although no human studies have been
performed yet. 52 A major benefit of being able to utilize an existing drug to target a
genetic alteration is that preclinical studies may not be required, and it is possible
that the drug may go straight to clinical trials. This can save a significant amount of
time and money in the development process, thereby making an effective drug available
sooner to patients.
PHARMACOGENOMICS CONSIDERATIONS DURING
PRECLINICAL STUDIES OF POTENTIAL LEAD DRUGS
Data from preclinical studies are usually needed to support an investigational
new drug (IND) application that, if approved, will allow for a drug to be tested in
patients. Initial studies typically use cell lines to assess drug efficacy and establish
effective dose ranges. Animal studies are then used to establish drug efficacy in vivo,
to optimize drug delivery and dosing, to confirm that the drug can hit its target
in vivo, and to identify potential adverse drug reactions (ADRs). Figure 4.3 provides
an overview of the types and sequence of preclinical studies that are used to generate
data to support an IND.