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

Pharmacoeconomics of Pharmacogenomics
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CYP2C9 and the Anticoagulant Warfarin
Warfarin anticoagulation therapy is increasing rapidly in the elderly population because
of the increasing prevalence of atrial fibrillation and longer life spans. In 2007, more
than 20 million new prescriptions were written for this drug in the United States,
according to the National Institutes of Health. Initiation and maintenance therapy of
warfarin is difficult because of wide intersubject variability in its dose requirements and
response, and thus warfarin dosing is monitored and adjusted to maintain appropriate
prothrombin time and international normalized ratio within a target range of 2–3 for
each patient. Warfarin is one of the first medications to be relabeled by the US FDA to
explain why an individual’s genetic make-up could affect response to the drug, and PGx
testing for warfarin is one of the first such tests to get US FDA approval.
Although warfarin is a generic medication that is relatively inexpensive and the cost
of testing for CYP2C9 and VKORC1 also seems to be relatively less expensive (ranging
from $250 to $630), the main cost of warfarin dosing is the healthcare spending
associated with bleeding complications and death, in particular during the first few
months of warfarin initiation therapy to titrate warfarin doses. Because adverse events
associated with warfarin therapy are common, and many are preventable through a
genotype-guided algorithm, the number of patients who could benefit more from the
PGx testing would be large, suggesting the presence of potential cost-effectiveness for
genotyping. In 34 eligible pharmacoeconogenomic articles published from 1999 to
2009, CYP2C9 alone or in combination with VKORC1 (vitamin K epoxide reductase
complex subunit 1) are the most common genes that were evaluated in the clinical
settings. 14 CYP2C9*2 or *3 variant alleles are associated with reduced maintenance
dose requirements of warfarin therapy and increased risk of major bleeding events; 35,36
the marginal cost per additional major bleeding event averted was estimated to be
$5778 for CYP2C9 genotype-guided dosing of warfarin, 37 and €4233 for CYP2C9 genotype-guided
dosing of acenocoumarol. 38 Testing of CYP2C9*2, *3 and VKORC1 A/A
before receiving warfarin was considered to have clinical validity 39 but unclear clinical
utility. 40,41 However, in atrial fibrillation patients treated with warfarin, the cost per
QALY gained was $60,725 and $170,000 for CYP2C9 and VKORC1 genotype-guided
dosing, respectively, 42,43 suggesting little cost-effectiveness. Currently, the US Centers
for Medicare and Medicaid Services have not found sufficient evidence to cover the cost
of genotyping for warfarin dosing. 44 In the future, multicenter, large-scale, prospective,
randomized clinical trials will be required to confirm whether genotype-guided warfarin
dosing would be less costly and more effective than its conventional regimen.
CYP2C19 and the Antiplatelet Drug Clopidogrel
Clopidogrel is a prodrug whose bioactivation is dependent largely on CYP2C19
activity in the liver (Figure 11.1), and thus the CYP2C19 genotype is the major predictor
of adverse cardiovascular events in clopidogrel-treated patients with acute
coronary syndrome (ACS) or those undergoing percutaneous coronary intervention
(PCI). 45 In 2010, the US FDA consecutively released the black box warning three
times for the clopidogrel labeling, alerting clinicians of the role of CYP2C19*2 and
*3 loss-of-function variants in response to that drug in patient care. Although the