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

Applying Pharmacogenomics in Drug Discovery and Development
83
% inhibition
Enzyme/receptor
Candidate
Step 1:
Identification of
genetic alterations
and target
validation
Step 2:
Drug discovery and
assessment of
“druggability”
Step 3:
In vitro assessment
of drug efficacy and
off-target effects
Step 4:
In vivo assessment
of drug efficacy and
toxicities
FIGURE 4.3 Preclinical studies of potential lead drugs. The impact of pharmacogenomics
on target identification (genomics analyses) and validation (cell line and animal studies), as
well as drug discovery and assessment of druggability (in silico, high-throughput screening,
and binding assays), were discussed in previous sections. Once these steps (steps 1 and 2,
respectively) are completed, and a lead drug is identified, in vitro and in vivo analyses are
performed to establish pharmacodynamic and pharmacokinetic characteristics for the drug.
These studies test drug efficacy, that is, how well the drug can hit its intended target and
inhibit disease initiation and/or progression. They also can help predict and/or identify drugrelated
toxicities. If these studies are successful (the drug has high efficacy and low toxicity),
then data collected can be used to support an IND that if approved will allow for subsequent
testing of the drug, in this diagram termed the candidate, in patients. (Adapted from
Hughes JP, et al., Br J Pharmacol, 162, 1239–49, 2011.)
As mentioned above, cell line and animal models that were developed to validate
a drug target as playing a causative role in disease initiation and/or progression
are extremely useful for testing drug efficacy in preclinical studies; the presence of
the target has already been confirmed in these models, and researchers will have
already established the sequence and timing of molecular and pathophysiological
changes that are associated with disease initiation and progression. Ideal cell lines
and animal models that have polymorphic variants of the target that are prevalent in
the patient population will have also been developed so that the impact of these on
drug efficacy can be assessed. In addition to assessing drug efficacy, identification
and minimization of the likelihood of ADR is a major focus during preclinical studies.
ADRs not only cause a significant number of deaths each year, but also increase
costs due to hospitalizations. In some instances, ADRs are severe and/or prevalent
enough to result in removal of a marketed drug. 53 ADRs can result from “off-target”
effects (the drug may target similar molecules that do not play a role in the disease
process, but play a critical role in systemic and/or organ function), a broad tissue
distribution of the target (the target molecule may be needed for the proper function
of other body systems), and/or from polymorphisms in drug-metabolizing enzymes.
The majority of ADRs are due to polymorphisms that cause dysfunction of phase I
and II enzymes involved in drug metabolism, although polymorphisms in drug