Improving Anticoagulant Therapy Through Warfarin Metabolite Profiling

Coumadin (R/S-warfarin) is a commonly prescribed anticoagulant for over 20 million Americans
for the treatment of atrial fibrillation, mechanical heart valves, venous thromboembolism
and other coagulopathies. While highly efficacious, warfarin treatment is challenging due to
a narrow therapeutic range and high inter-individual variations in response. Optimal
warfarin dosage relies on a potentially lengthy trial-and-error process to optimize dosage
for a desired anticoagulant response as measured by the international normalization ratio
(INR), a prothrombin test. Even when a maintenance dose is achieved, patients are prone to
testing out of the target INR range, and thus are at risk of hemorrhaging (over-dosing) or
thromboembolism (under-dosing). In fact, warfarin is among the top ten drug-related causes
of serious adverse drug events and increased health care costs. The progressive increase in
warfarin use necessitates a better understanding of the mechanisms underlying
inter-individual variability in responses to anticoagulant therapy. Our long-term goal is to
identify metabolic biomarkers correlating with clinical responses to warfarin therapy and
then utilize this knowledge to predict safe and effective dosing for patients based on a
single blood draw.

Therapeutic outcomes for patients involve a balance between warfarin dosing and its
metabolism to maintain a stable target INR. There is an initial lengthy titration stage in
which dosing is increased to achieve but not surpass a target INR range. The potency of this
effect depends on warfarin metabolism, which counters the dosing effect on patients by
inactivating the drug. Warfarin undergoes extensive metabolism through distinct enantio- and
regio-specific metabolic pathways to yield a complex array of essentially inactive isomeric
metabolites. Warfarin is clinically available as an equal mixture of R and S enantiomers.
S-Warfarin is about four times more potent than R-warfarin, and presumably dominates the
anticoagulant response to therapy. During maintenance dosing, a longer metabolic half-life
for R-warfarin leads to higher accumulation levels in plasma than those observed for
S-warfarin. Variations in R-and S-warfarin plasma levels may potentiate the anticoagulant
effect of both drug isomers and the corresponding responses to therapy. For our exploratory
study, we will identify biomarkers within patient metabolic profiles for R-and S-warfarin
that predict clinical outcomes for the patients.

Inclusion Criteria:

1. Males aged 60 - 69 originally. Opened inclusion criteria age to include 18-79 years
of age.

2. Potential participant received a warfarin maintenance dose with a stable INR (defined
as within target range over a two month (60 day) period that includes a minimum of
two clinical visits).

3. Potential participant has taken warfarin as prescribed over the past three days.

Exclusion Criteria:

1. Female

2. Potential participant receiving a warfarin while not achieving a stable INR (defined
as within target range over a two month (60 day) period that includes a minimum of
two clinical visits).

3. Potential participant has not received any warfarin over the past three days.