8. Background - Warfarin
• Mechanism: Inhibits
regeneration of vitamin
K(1) epoxide, inhibiting
synthesis of vitamin K-
dependent clotting
factors in liver
• Peak response: Full
anticoagulant effect in
72-96 hours
9.
10. Background - Warfarin
• Monitoring: International
Normalized Ratio (INR)
– Measurement of extrinsic pathway
activity
– Goal INR 2-3 (sometimes 2.5-3.5)
– Low INR: increased clotting risk
– High INR: increased bleeding risk
• Indications: Atrial fibrillation,
deep vein thrombosis,
pulmonary embolism,
cerebrovascular accident, many
others
11. Background - Warfarin
• Dosing: Algorithms vary widely
– Common dose/day= 5mg
• Dose Variations:
– <1mg daily to >20mg daily
Dose related side effects:
Nose bleeds to death
12. Background - Warfarin
• R-warfarin metabolism
– CYP1A2 to 6- and 8-
hydroxywarfarin
– CYP3A4 to 10-hydroxywarfarin
– Carbonyl reductases to alcohols
• S-warfarin metabolism
– CYP2C9 to 6- and 7-
hydroxywarfarin
• Relative potencies: S-isomer ~3
times more potent that R-isomer
13. Background – Warfarin Interactions
• Drug-drug interactions
– Enzyme inhibition /
induction:
• CYP2C9
• CYP3A4
• CYP1A2
– Alteration of intestinal flora
• Drug-diet interactions:
– Vitamin K
– Alcohol
– Smoking
Warfarin is the most widely used oral anticoagulantWarfarin is the most widely used oral anticoagulant
agent worldwide; more than 30 million prescriptionsagent worldwide; more than 30 million prescriptions
were written for this drug in the United States in 2004were written for this drug in the United States in 2004
15. Standard Dosing Algorithm
• Standard Dosing:
– Days 1,2: 10mg daily; 5mg thereafter or per
INR
– INR measured days 0, 3, 5, 8, 21, 60, 90,
and as clinically indicated
– Adjusted dose given beginning Day 3 based
on algorithm
16. Standard Dosing Algorithm
INR
1.0-1.59
-Inquire about s/sx of clotting, refer to appropriate care,
give extra dose (average day 5-7 dose for day 8)
-Increase weekly dose by 10%
-INR in 5 days, 14 days
INR
1.6-1.79
-Extra half dose today (average of days 5-7 for day 8)
-Increase weekly dose by 5%
-INR in 7 days, 14 days
INR
1.8-1.99
1st Time:
-INR in 14 days
Repeat:
-Increase weekly dose by 5%; INR in 14 days
INR
2.0-3.0
-INR in 14 days after day 8, then monthly
INR
3.01-3.39
1st Time:
-INR in 14 days
Repeat:
-Decrease weekly dose by 5%; INR in 14 days
INR
3.4-4.99
-Reduce today’s dose by a half if INR <4, omit if >=4.
-Decrease weekly dose by 10%
-INR in 7 days, 14 days
INR
> 5.0
-Inquire about s/s bleeding, refer to an appropriate
facility for care. Omit 2 doses
-INR in 48 hours
-When retested INR falls into 1.8-3.39 range, decrease
weekly dose by 15%; INR in 7 days, 14 days
-If INR>9, follow special protocol
19. Genetics and warfarin response
• CYP2C9:
– Two SNPs impair metabolism of S-warfarin:
– *2 and *3 alleles are associated with increased
bleeding and decreased warfarin requirement
– *2 and *3 variants are found in 11% and 8% of whites
and 3% and 0.8% of blacks
– Patients who are homozygous for the wild type allele
(CYP2C9*1), S-warfarin is cleared normally, resulting
in a modest elevation of the INR.
20. CYP2C9 SNPs
• CYP2C9*2 is the SNP in exon 3
(CGT>TGT)
• CYP2C9*3 is in exon 7 (ATT>CTT)
• Patients with one or two of these SNPs
have reduced warfarin requirements and
a 2-to 3-fold elevated risk of an adverse
event when beginning warfarin.
23. Genetics and warfarin response
• Vitamin K Epoxide Reductase Group 1
(VKORC1):
– Location: Chromosome 16 (16p11)
– Prior study of intron 1 SNP rs9934438
(C1173T):
• Warfarin requirement higher (6.2mg) among CC
patients than in CT (4.8 mg) or TT (3.5 mg).
Approximate population frequencies CC 37%, CT
50%, TT 13%
– More recently, 10 common SNPs, all
noncoding, divide into 5 haplotypes which form two
distinct evolutionary groups.
24. Genetics and warfarin response
• 2 Major VKORC1 haplotypes:
– Designated A (“low dose”) and B (“high dose”):
• A/A: 2.7mg/day
• A/B: 4.9mg/day
• B/B: 6.2mg/day
• Haplotype data as informative as single SNPs
27. Genetics and warfarin response
• FDA, August 16, 2007:
– Package insert for warfarin changed to
include information on CYP2C9 and VKORC1
genotyping and their role in determining drug
clearance and steady-state dose
requirements
– “lower initiation doses should be considered
for patients with certain genetic variations in
CYP2C9 and VKORC1 enzymes as well as
for elderly and/or debilitated patients and
patients with potential to exhibit greater than
expected PT/INR responses to COUMADIN”
28. Incidence of CYP2C9 and
VKORC1 SNPs(%)
Caucasian African-
American
Other Asian
CYP2C9 *2 13.1 5.2 10.4 0
CYP2C9 *3 6 1 4.2 4
VKORC1
Group A
36.6 9.5 41.7 85
VKORC1
Group B
63.4 90.5 58.3 14
29. Advantages of PG
• Majority of the variance can be predicted using
genes and several clinical factors –
“personalized medicine”
• Genetic platforms available
• Fewer surprises
– Faster to stable INR
– Less AE’s
– More time in range over first 30 days
• Patient acceptance high
• Web or computer based dosing guidance
available
30. Barriers to PG
• Not many multi-centered RCT
• Unknown benefit in some patient
populations
• Cost
• Availability
• Clinician knowledge
• Potential delay in medication initiation
31. CYP2C9 Genotype-Guided Warfarin
prescribing enhances the efficacy and
safety of Anticoagulation
• A Prospective Randomized Controlled
Study
• Patients were randomly assigned to
receive Warfarin by a validated algorithm
(“control”, 96 patients) or CYP2C9
genotype-adjusted algorithms (“study”’ 95
patients).
34. Pharmacodynamic end points
• In the study group first therapeutic INR
was reached 2.73 days earlier than in the
control group.
• Warfarin cumulative dose until first
therapeutic INR was achived was 41.7%
higher in the control group, but it was
given over a longer period of time,
average Warfarin daily dose was 22%
lower in the study group.
37. Pharmacodynamic end points
• The use of higher daily dose in the study group was not
associated with higher rate of over anticoagulation
(INR>3).
• The percent time spent within the therapeutic range was
1.85-fold higher in the study group.
• Among patients in the control group, time to first
therapeutic INR, total Warfarin dose, and average daily
Warfarin dose did not vary across the 3 major genotypic
groups.
• Among patients in the study group as expected from the
study design, Warfarin cumulative dose and average
daily dose up to therapeutic INR were dependent on
CYP2C9 genotype (p=0.01, and<0.001 respectively)
38.
39. Stabilization phase
• Pharmacodynamic steady state was
reached in the study group after 22.1+-6.9
days and 18.1 days earlier than in the
control group 40.2+-21.1 days p<0.001.
• Time required to achieve stable
anticoagulation were significantly different
between the study and the control groups
(p<0.001)
40.
41.
42. Stabilization phase
• Enhanced pace of stabilization in the study
group was associated with significantly reduced
number of days spent outside the therapeutic
range and significantly higher percent of time
spent within the range (P<0.001)
• This was accounted for by 4- and 3.7- fold lower
number of days spent below and above the
recommended range, respectively (P<0.001).
• Total number of performed INR tests was more
than twice as much as lower in the study group
(P<0.001).
43. Stabilization phase
• Warfarin daily dose required to maintain
adequate anticoagulation varied across
the 3 major CYP2C9 genotype groups’ so
that patients carrying a single or two
variant allele (s) required 77 and 52% of
the dose used by CYP2C9*1
homozygotes (p<0.03 and<0.001
respectively)
44.
45. Pharmacokinetics
• In homozygotes for the wild –type allele the mean oral
clearance of S-Warfarin was 4.03+-2.19 ml/min and was
significantly greater than in carriers of either a single allele
(2.96+-1.67 ml/min, p<0.02) or two variant alleles(0.98+-
0.41 ml/min, p<0.01).
• Mean S/R Warfarin ratio was 0.35+-0.11 among CYP2C9*1
homozygoted and was significantly lower than that in
heterozygotes (0.54+-0.35,p<0.001) or carriers of two
mutated alleles (1.02+-0.45, p<0.001).
• The number of variant alleles was inversely correlated with
S-Warfarin oral clearance (r=0.417,p<0.01) and directly
correlated with S/R Warfarin ratio (r=0.552,p<0.01).
55. Randomized Trial of genotype-guided
versus standard Warfarin dosing in
patients initiating oral anticoagulation
• Genotypes of CYP2C9 And VKORC1 conjointly
determine Warfarin dose requirements.
• CYP2C9*2 and CYP2C9*3 cause reductions in
enzymatic activity of 30% and 80% respectively.
• Ten VKORC1 SNPs, many tightly linked, and 5
inferred haplotypes determine low, intermediate
and high dose requirements.
• Together these genotypes plus clinical
characteristics predict approximately one half of
inter-individual dose variability.
56. Warfarin dosing pharmacogenetic
arm
•Included CYP2C9 ( *1, *2, *3) and
VKORC1 (C1173T) genotypes, age,
weight, and sex: estimated weekly dose
(y)=1.64+exp 3.894+*1*1(0)+*1*2(-
0.917)+*1*3(-0.360)+*2*3(-0.947)+*2*2(-
0.265)+*3*3(-1.892)+VK-CT(-0.304)+VK-
TT(-0569)+VK-CC(0)+AGE(-0.009)+
MALE SEX(0.094)+FEMALE SEX(0)+
WEIGHT IN Kg(0.003).
Notas del editor
s/s of clothing – pain or swelling in the legs, sob., chest pain, new focal weakness or numbness, slurred speech, vision changes etc.
s/s** bleeding – nose bleeds, unusual bruising, dark stools, pink or bloody urine, excessive menstruation, blood in the sputum etc.