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

18 Applying Pharmacogenomics in Therapeutics
decreased CYP2C9 enzyme activity, resulting in impaired warfarin metabolism
and increased risk of bleeding. 139,140 The VKORC1 1173 C>T or VKORC1-1639 G>A
polymorphism affects the formation of vitamin K–dependent clotting factors. 141
Clinical Relevance
The US FDA has approved dosing information based on pharmacogenomic testing
for the brand name product of warfarin (Coumadin ® ). 131 Patients with CYP2C9*2 or
CYP2C9*3 alleles may have decreased CYP2C9 activities by 50–90%, thus requiring
lower warfarin doses. 139,140 Haplotype A from VKORC1 SNPs is associated with
lower warfarin dose requirements, and haplotype B is associated with higher warfarin
dose requirements. 141,142 Patients with the VKORC1 A/A genotype are more likely
to require a lower weekly warfarin dose of 32%; those with the B/B genotype are
likely to require an increased weekly warfarin dose of 35%. 143
Warfarin pharmacogenomic testing is helpful in guiding dosing decisions for
patients who are either sensitive or resistant to the drug therapy. In a multicenter clinical
trial conducted by the International Warfarin Pharmacogenetics Consortium, 4043
patients taking warfarin were randomized to three algorithms— pharmacogenetic,
clinical, and fixed dose (35 mg/week) approaches. The study demonstrated that
the pharmacogenetic algorithm group showed more accurate dose estimates than
the other two dosing algorithms, particularly for patients requiring a total weekly
dose of <21 mg or >49 mg. 144 Warfarin pharmacogenomic testing may help patients
minimize bleeding risks although the supporting evidence is conflicting. 145 The risk
of bleeding in patients with at least one allele variant of CYP2C9 can increase two- to
threefold during the initiation phase of therapy; however, the evidence for the risk of
bleeding in patients during long-term therapy is conflicting. 74,133,146,147
Testing Availability and Recommendations
Pharmacogenomic testing for CYP2C9 and VKORC1 may help improve prediction of
warfarin target maintenance doses. 143 Not all patients with polymorphisms in CYP2C9
or VKORC1 will have a serious bleeding event; those without any polymorphism may
still be susceptible to having a bleeding event due to clinical, nongenetic factors. There
are several FDA-approved pharmacogenomic tests that detect both CYP2C9 and
VKORC1 polymorphisms. Pharmacogenomics testing may be cost-effective in helping
patients achieve an optimal therapeutic dose and avoid unnecessary bleeding risks. 148
EDUCATIONAL RESOURCES
Several professional organizations have reviewed, compiled, and endorsed competencies
for pharmacogenomic education. In 2001, the National Coalition for Health
Professional Education in Genetics (NCHPEG), representing a working group of
specialists with experience in genetics and health professions, identified core competencies
in genetics for healthcare professionals. In 2007, 18 core competencies were
updated to encourage healthcare professionals to “integrate genetics knowledge,
skills, and attitudes into routine health care.” 149