Pharmacogenetics of dabigatran etexilate interindividual variability.
BACKGROUND
Dabigatran etexilate is given in fixed doses without coagulation monitoring for the prevention of blood clots in at risk adults. A high inter-individual variability in blood concentrations of the active metabolite of dabigatran has been reported. ABCB1 and CES1 exert an important effect in the metabolism of dabigatran etexilate and allele variants at these two loci are likely to play a pivotal role. To investigate whether screening for polymorphisms within the ABCB1 and the CES1 genes would explain a portion of the inter-individual variability in blood concentrations of the active metabolite of dabigatran.


METHODS
In a cohort of patients who had atrial fibrillation and on anticoagulant prophylaxis with dabigatran etexilate, we investigated whether genotypes at rs4148738 (ABCB1), rs8192935 (CES1), and rs2244613 (CES1) loci would affect plasma dabigatran trough and peak concentrations.


CONCLUSIONS
Among 92 patients (median age: 72.0years, range: 52-92) analyzed, no clinical variable or genotype was associated with a significant difference in dabigatran peak concentrations. As for trough concentrations, in addition to creatinine clearance, and sex a significant association with the CES1 SNP rs8192935 (p=0.023) was detected. The mean adjusted plasma levels were higher among patients with the CC genotype (86.3ng/dl) than in those carrying the T allele (62.1ng/dl). No significant effect was found for the ABCB1 SNP rs4148738. The CES1 SNP rs8192935 significantly influenced the dabigatran trough concentrations and carriers of the T allele showed significantly lower concentrations than did carriers of the CC genotype.
Medical Genetics, Dept. of Clinical and Experimental Medicine, University of Foggia, Italy.
Claudia
C
Dimatteo
Medical Genetics, Dept. of Clinical and Experimental Medicine, University of Foggia, Italy.
Giovanna
G
D'Andrea
Atherosclerosis and Thrombosis Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Italy.
Gennaro
G
Vecchione
Haemostasis and Thrombosis Center, Department of Laboratory Medicine, AO Istituti Ospitalieri, Cremona, Italy.
Oriana
O
Paoletti
Atherosclerosis and Thrombosis Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Italy.
Filomena
F
Cappucci
Medical Genetics, Dept. of Clinical and Experimental Medicine, University of Foggia, Italy.
Giovanni Luca
GL
Tiscia
Hematology Service, ASL Foggia, Italy.
Matteo
M
Buono
Atherosclerosis and Thrombosis Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Italy.
Elvira
E
Grandone
Haemostasis and Thrombosis Center, Department of Laboratory Medicine, AO Istituti Ospitalieri, Cremona, Italy.
Sophie
S
Testa
Medical Genetics, Dept. of Clinical and Experimental Medicine, University of Foggia, Italy. Electronic address: m.margaglione@unifg.it.
Maurizio
M
Margaglione
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D000069604:Dabigatran / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000991:Antithrombins; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D000069604:Dabigatran
Dabigatran; Genetics; Oral anticoagulants; Polymorphisms