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

Clinical Applications of Pharmacogenomics in Cancer Therapy
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TABLE 6.2
PGx Biomarkers for the Prevention of Toxicity in Cancer Therapy
PGx
Biomarkers Therapeutic Agents PK/PD Impact
UGT1A1 9 Irinotecan, nilotinib UGT1A1*28: increased
systemic exposure to
SN-38.
DPD 10,11 Fluorouracil (5-FU),
capecitabine
Heterozygosity of
DYPD*2A allele increases
the systemic exposure
to 5-FU.
TPMT 3,12 6-Mercaptopurine (6-MP) TPMT inactivates 6-MP.
Low or absent TPMT
activity increases systemic
exposure to 6-MP.
CYP3A4/3A5 13–15 Cyclophosphamide Activates the prodrug to its
active form.
CYP2B6 13–15 Cyclophosphamide, ifosfamide CYP2B6 is a major
drug-metabolizing
enzyme for
cyclophosphamide
and ifosfamide.
Frequency of Affected
Phenotype Clinical Significance
Deficiency of the enzyme may
occur in 35% of white and black
Americans.
3% of the white population may
have deficient enzyme activity.
Approximately 10% of white
patients are PMs of this enzyme,
and 0.3 % have complete
deficiency of the enzyme activity
CYP3A5*3: a variant allele occurs
in 45% of black Americans and
9% of whites.
Exact frequency is unknown, but
48 different alleles have been
identified.
UGT1A1*28 /*28: increased risk for
developing severe diarrhea, and
neutropenia at doses >200 mg/m 2 .
(TA) 7 /(TA) 7 : increased risk of nilotinibinduced
hyperbilirubinemia.
Deficiency can lead to fatal neurological
and hematological toxicities, grade 3
diarrhea, and hand–foot syndrome
associated with FU plasma levels
>3 μg/mL in males.
Patients with low or absent TPMT activity
are at increased risk for developing severe,
life-threatening myelotoxicity. Dose
adjustment is required.
Deficiency of this enzyme causes
interindividual variability in efficacy and
enhanced toxicity.
Standard dosing for patients with
dysfunctional CYP2B6 may be at
increased risk for nephrotoxicity.
(Continued)