Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study
Background Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of CYP2C9 , VKORC1 , and CYP4F2 on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin ti...
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Veröffentlicht in: | Pharmacological reports 2021-10, Vol.73 (5), p.1405-1417 |
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Sprache: | eng |
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Zusammenfassung: | Background
Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of
CYP2C9
,
VKORC1
, and
CYP4F2
on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin time international normalized ratio (PT-INR), and log-INR variability.
Methods
A cross-sectional study was conducted in non-smoking adults receiving warfarin for at least 6 months. Their demographics, diagnoses, warfarin dosing regimen, concomitant drugs, PT-INR, and bleeding episodes were obtained.
CYP2C9
(rs1057910-*3 and rs1799853-*2 alleles),
CYP4F2
(rs2108622), and
VKORC1
(rs9923231) polymorphisms were assessed using real-time polymerase chain reaction. Three genotype groups (I-III) were defined based on the combined genetic polymorphisms of
CYP2C9
and
VKORC1
from the FDA’s recommendations. Key outcome measures included anticoagulation control, time spent in therapeutic range, stable warfarin dose, WSI, log-INR variability, and Warfarin Composite Measure (WCM).
Results
The study recruited 236 patients; 75 (31.8%) carried a functional
CYP2C9
variant allele, and, 143 (60.6%) had at least one T allele in
CYP4F2
and 133 (56.4%) had at least one T allele in
VKORC1
. Groups’ II and III
CYP2C9
and
VKORC1
genotypes were observed with reduced stable warfarin dose, increased WSI, higher log-INR variability, and increased bleeding risk. The presence of *2 or *3 allele in
CYP2C9
was observed with reduced stable warfarin doses akin to the presence of T alleles in
VKORC1
; however, the doses increased with T alleles in
CYP4F2
.
Conclusion
The evaluated genetic polymorphisms significantly influenced all the pharmacodynamic parameters of warfarin. Evaluating
CYP2C9
,
VKORC1
, and
CYP4F2
genetic polymorphisms prior to warfarin initiation is likely to optimize therapeutic response.
Graphic abstract |
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ISSN: | 1734-1140 2299-5684 |
DOI: | 10.1007/s43440-021-00256-w |