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

Applying Pharmacogenomics in Drug Discovery and Development
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TABLE 4.1 (Continued)
Pharmacogenomic Data and Testing Information for FDA-Approved Drugs
Clinical Specialty Drug Used Associated Genes
Ophthalmology Timolol CYP2D6
Psychiatry
Aripiprazole, atomoxetine,
chlordiazepoxide and amitriptyline,
citalopram (1), citalopram (2),
clomipramine, clozapine,
desipramine, diazepam, doxepin,
fluoxetine, fluoxetine and olanzapine,
fluvoxamine (1), fluvoxamine (2),
fluvoxamine (3), iloperidone,
imipramine, modafinil (1),
modafinil (2), nefazodone,
nortriptyline, paroxetine, perphenazine,
pimozide, protriptyline, risperidone,
thioridazine, trimipramine, valproic
acid, venlafaxine
Pulmonary Tiotropium CYP2D6
Reproductive
Drospirenone and ethinyl estradiol
clomiphene, tolterodine
CYP2D6, CYP2D6, CPY2D6,
CYP2C19, CYP2D6, CYP2D6,
CYP2D6, CYP2D6, CYP2C19,
CYP2D6, CYP2D6, CYP2D6,
CYP2C9, CYP2C19, CYP2D6,
CYP2D6, CYP2D6, CYP2C19,
CYP2D6, CYP2D6, CYP2D6,
CYP2D6, CYP2D6, CYP2D6,
CYP2D6, CYP2D6, CYP2D6,
CYP2D6, UCD (NAGS; CPS;
ASS; OTC; ASL; ARG),
CYP2D6
CYP2C19, Rh genotype,
CYP2D6
Rheumatology Azathioprine, flurbiprofen TPMT, CYP2C9
Sources: Adapted from Gullapalli RR, et al., J Pathol Inform, 3, 40, 2012; data source: http://www.
fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm.
a
Numbers in the brackets indicate that the drug is affected by multiple genetic polymorphisms.
been identified. For example, it is now well known that the metabolism of tricyclic
antidepressant drugs is dependent on CYP2D6, and to some extent CYP2C19, and
polymorphisms in these enzymes can affect both efficacy and toxicity. As adverse
effects occur quite frequently for this drug class, this has led to increased usage
of pharmacogenomic testing for polymorphisms in these enzymes. An increasing
number of pharmacogenomic tests are also being developed for existing drugs
that are known to have substantial interpatient dose variability and high rates of
adverse reactions. 71 A good example is warfarin. Approximately 20% of patients
taking warfarin are hospitalized within the first six months of usage due to bleeding
events. Warfarin is metabolized by CYP2C9, a highly polymorphic enzyme.
The major two allele variants encoding this enzyme, CYP2C9*2 and CYP2C9*3,
are present in the patient population, and have been shown to account for approximately
12% of the interpatient variability for warfarin. Patients homozygous for
the CYP2C9*1 variant are extensive metabolizers, while patients who homozygous
for CYP2C9*3 are poor metabolizers. Patient with the following genotypes
are intermediate metabolizers: CYP2C9*1/*3 and CYP2C9*1/*2. While the
results of three recent clinical studies are conflicting, pharmacogenomic testing