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

84 Applying Pharmacogenomics in Therapeutics
transporters often also play a role. 54–58 As discussed in the above sections, in silico
studies that are used to identify lead drugs and assess “druggability” can be used
to help predict ADRs, but these are not infallible and often false negatives slip
through. 59 Cell line studies may also be used to help predict some ADRs; however,
animal studies usually provide the strongest evidence for prediction of ADRs in
patients as all absorption, distribution, metabolism, and excretion (ADME) effects
can be assessed in a system that is similar to a patient. 60,61 In a typical animal
model toxicity study, the impact of a high- and low-dose drug regimen on toxicity
is compared to a vehicle control. Toxicity may be assessed by physical examination
of the animals, serum biochemistry, hematological analysis, and urinalysis as
well as histopathological analysis of certain tissues including the liver and kidney.
If toxicity is observed, molecular studies may then be performed to better
understand the underlying molecular mechanisms involved. If a particular enzyme
responsible for the ADME of the drug is polymorphic, appropriate cell line and animal
models should be tested to determine the impact of prevalent polymorphisms
on drug toxicity.
The majority of ADRs that result from polymorphisms in ADME genes are
identified after approval of the drug. This is usually due to lack of inclusion
of pharmacogenomic studies in the drug development process, or because the
pharmacogenomic studies that had been conducted were not sufficiently powered
to detect these ADRs. Irinotecan, a DNA topoisomerase I inhibitor that is used
to treat patients with lung or colorectal cancer, is a good example. Following
FDA approval, a significant number of patients were found to experience severe
leukopenia and/or diarrhea. These ADRs have not occurred at significant rates
in clinical trials of irinotecan when it was first used in the general population.
An initial pharmacogenomic analysis of specimens collected from patients who
experienced these ADRs versus those who did not experience them revealed that
15% of ADR patients were homozygous for the UGT1A1*28 allele and 33% were
heterozygous. 62 UGT1A1, a phase II enzyme, glucoronidates the active metabolite
of irinotecan (SN-38), and thereby mediates its excretion from the body.
Subsequent studies confirmed that polymorphisms in UGT1A1 are responsible
for irinotecan ADRs, 63,64 and the FDA now strongly recommends pharmacogenomic
testing for UGT1A1*28 and corresponding dosage adjustments. It is very
likely that the inclusion of pharmacogenomic testing during the development of
irinotecan could predict these UGT1A1-related ADRs and hence would minimize
or avoid them.
PHARMACOGENOMICS AND CLINICAL STUDIES
Once an IND gets approved, clinical studies can be performed to assess drug efficacy
and toxicity in patients. Phase I studies are used to establish tolerated dose
ranges, to assess pharmacokinetics, and to identify any major ADR. Phase II
studies are primarily geared to test drug efficacy, and phase III studies test drug
effectiveness although ADRs are monitored simultaneously. Ideally, pharmacogenomic
samples and data should be collected throughout the clinical trial process to
help maximize drug efficacy and minimize potential harm to patients by using the