Abstract
Excepting host genetic factors, other influences on the pharmacokinetic and pharmacodynamic behavior of warfarin are subject to variations during the treatment despite attempts to stabilize the INR. In 214 Omani patients on warfarin therapy, we evaluated the extent of influence of known genetic predictors of warfarin dose variability, namely CYP2C9, CYP4F2 and VKORC1 gene polymorphisms in a genetically heterogeneous patient population. When patients were stratified according to their daily warfarin maintenance dose (to maintain INR between 2 and 3) into “low dose” (sensitive), “medium dose” (intermediate) and “high dose” (resistance) groups, overall, seven patients with three or four mutant alleles fell in the sensitive group and consequently 25% (7 out of 28) of at risk patients for over anticoagulation can be recognized by prospective pharmacogenetic testing in this patient population. Pre-prescription genotyping of these loci prior to therapy initiation will therefore benefit a small fraction of this population.
Highlights
Warfarin is one of the most widely used anticoagulants with a narrow therapeutic index; small warfarin dose variations in a subset of individuals could have adverse drug reactions (ADRs) and result in either hemorrhage or failure to prevent thrombotic complications. [1] In order to avoid ADRs, the traditional warfarin dose adjustment relied on a trial-and-error basis by administering an initial dose of 5 mg or 10 mg, [2,3] with subsequent dose adjustment depending upon the international normalized ratio (INR) response until the desired stable INR values were obtained on three consecutive visits
In 214 Omani patients on warfarin therapy, we evaluated the extent of influence of known genetic predictors of warfarin dose variability, namely CYP2C9, CYP4F2 and VKORC1 gene polymorphisms in a genetically heterogeneous patient population
When patients were stratified according to their daily warfarin maintenance dose into “low dose”, “medium dose” and “high dose” groups, overall, seven patients with three or four mutant alleles fell in the sensitive group and 25% (7 out of 28) of at risk patients for over anticoagulation can be recognized by prospective pharmacogenetic testing in this patient population
Summary
Warfarin is one of the most widely used anticoagulants with a narrow therapeutic index; small warfarin dose variations in a subset of individuals could have adverse drug reactions (ADRs) and result in either hemorrhage or failure to prevent thrombotic complications. [1] In order to avoid ADRs, the traditional warfarin dose adjustment relied on a trial-and-error basis by administering an initial dose of 5 mg or 10 mg, [2,3] with subsequent dose. Studies involving genome-wide scan have consistently shown that the genetic contribution to warfarin dose requirement is restricted to three polymorphic loci, namely CYP2C9, CYP4F2 and VKORC1 [4,5]. Polymorphisms in these three loci vary in frequency across populations, [6,7] and the relative contribution of the CYP2C9, CYP4F2 and VKORC1 genotypes to the estimates of warfarin dose will vary. In the present study we analyzed the frequency distribution of warfarin dose-predictive (warfarin sensitive as well as warfarin resistant) genetic polymorphisms in the CYP2C9, CYP4F2 and VKORC1 loci in a micro-geographicallydefined, ethnically admixed Omani patients on warfarin. We assessed the proportion of Omani patients who will benefit directly from prospective pharmacogenetic testing especially as a locally developed pharmacogenetic algorithm in patients on warfarin could explain 63% dose variability [11]
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