Effect of cilostazol on optimized standard antiplatelet therapy in a patient with a cytochrome P450 2C19 *2/*2 genotype

2010 ◽  
Vol 26 (1) ◽  
pp. 79-82 ◽  
Author(s):  
Qiang Fu ◽  
Nobuaki Suzuki ◽  
Kaoru Takada ◽  
Hirosada Yamamoto ◽  
Shuichi Ishikawa ◽  
...  
Author(s):  
Scott L Charland ◽  
Barnabie C Agatep ◽  
Daniel C Malone ◽  
Eric J Stanek

OBJECTIVES: Cytochrome P450 2C19 (CYP2C19) genotype has been shown to affect cardiovascular (CV) outcomes for clopidogrel but not prasugrel. This study evaluates the cost-effectiveness of CYP2C19-guided vs. routine antiplatelet therapy in ACS patients. METHODS: We constructed a literature-based, decision analytic, Markov model (TreeAge 2009) to estimate the cost-effectiveness of CYP2C19-guided aspirin plus either clopidogrel or prasugrel therapy vs. no genotyping. Post-initial ACS CV events were based on the TRITON-TIMI 38 study and related costs were derived primarily using 2007 Healthcare Cost and Utilization Project DRGs for nonfatal MI and stroke, CV death, intracranial hemorrhage, other life-threatening bleed, and minor bleed. Additional costs and disease-state utilities were obtained from other published sources. All costs were adjusted to 2009 $US using the Consumer Price Index medical care component. The model allowed for clopidogrel/prasugrel discontinuation and aspirin monotherapy. Model sensitivity was assessed using 1-way and multi-way analysis of influential parameters. RESULTS: The base case model demonstrated that CYP2C19 genotype guided antiplatelet therapy yielded lower overall annual cost and greater efficacy vs. no genotyping ( Table ). The model was sensitive to (in declining order): clopidogrel cost/day ($1 to $5.78), prasugrel cost/day ($4.09 to $ 6.81), % CYP2C19 extensive metabolizers on clopidogrel (60% to 100%), CYP2C19 test cost ($60 to $250), and monthly CV event management cost. A threshold value for clopidogrel at <$2.14/day favored the no genotyping strategy. However, the genotyping strategy was dominant when clopidogrel cost =$1/day and a CYP2C19 test cost threshold of <$125 on 2-way analysis. CONCLUSIONS: CYP2C19 genotype-guided clopidogrel or prasugrel therapy is cost-effective for up to 1 year in ACS patients, and can remain a preferred strategy at a hypothetical generic clopidogrel cost of $1.00/day. Table Strategy1 Annual Cost Incremental Cost Quality Adjusted Life Year (QALY) Incremental QALY Cost/QALY Incremental Cost Effectiveness (ICER) CYP2C19 Genotype-Guided $ 3,211 0.7212 $ 4,452 No Gentoyping $ 3,331 $120 0.6767 - (0.0445) $ 4,921 (Dominated) 1Base case values:Drug wholesale acquisition cost/day: clopidogrel $4.62, prasugrel $5.45; Baseline post-ACS utility = 0.83; Monthly cost for post-CV event management = $351; CYP2C19 genotyping =$185; After genotyping: 80% of extensive metabolizers, 20% of intermediate metabolizers and 10% of poor metabolizers on clopidogrel; 80% on clopidogrel without genotyping; Willingness to pay = $200


2013 ◽  
Vol 19 (13) ◽  
pp. 2489-2495 ◽  
Author(s):  
George Kassimis ◽  
Eleana F. Stavrou ◽  
Dimitrios Alexopoulos ◽  
Aglaia Athanassiadou

2020 ◽  
Vol 76 (5) ◽  
pp. 479-486
Author(s):  
Takashi Ishimatsu ◽  
Ken-ichiro Sasaki ◽  
Tatsuyuki Kakuma ◽  
Atsushi Harada ◽  
Yuji Hirakawa ◽  
...  

Xenobiotica ◽  
2009 ◽  
Vol 00 (00) ◽  
pp. 090901052457079-8
Author(s):  
Y. Nishiya ◽  
K. Hagihara ◽  
A. Kurihara ◽  
N. Okudaira ◽  
N.A. Farid ◽  
...  

2020 ◽  
Vol 13 (3) ◽  
pp. 233-244
Author(s):  
Amelia Nathania Dong ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Beow Chin Yiap ◽  
...  

Background: There is a large inter-individual variation in cytochrome P450 2C19 (CYP2C19) activity. The variability can be caused by the genetic polymorphism of CYP2C19 gene. This study aimed to investigate the molecular and kinetics basis for activity changes in three alleles including CYP2C19*23, CYP2C19*24 and CYP2C19*25found in the Chinese population. Methods: The three variants expressed by bacteria were investigated using substrate (omeprazole and 3- cyano-7-ethoxycoumarin[CEC]) and inhibitor (ketoconazole, fluoxetine, sertraline and loratadine) probes in enzyme assays along with molecular docking. Results: All alleles exhibited very low enzyme activity and affinity towards omeprazole and CEC (6.1% or less in intrinsic clearance). The inhibition studies with the four inhibitors, however, suggested that mutations in different variants have a tendency to cause enhanced binding (reduced IC50 values). The enhanced binding could partially be explained by the lower polar solvent accessible surface area of the inhibitors relative to the substrates. Molecular docking indicated that G91R, R335Q and F448L, the unique mutations in the alleles, have caused slight alteration in the substrate access channel morphology and a more compact active site cavity hence affecting ligand access and binding. It is likely that these structural alterations in CYP2C19 proteins have caused ligand-specific alteration in catalytic and inhibitory specificities as observed in the in vitro assays. Conclusion: This study indicates that CYP2C19 variant selectivity for ligands was not solely governed by mutation-induced modifications in the active site architecture, but the intrinsic properties of the probe compounds also played a vital role.


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