Safety of dabigatran in patients with atrial fibrillation and chronic kidney disease: pharmacokinetic and pharmacogenetic aspects
A. I. Skripka,
P. O. Bochkov,
K. A. Akmalova,
R. V. Shevchenko,
P. M. Krupenin,
V. V. Kogay,
A. I. Listratov,
A. S. Krainyaya,
D. A. Napalkov,
O. S. Gurinovich,
A. A. Sokolova,
V. V. Fomin,
D. A. Sychev https://doi.org/10.21518/2079-701X-2019-21-65-73
Abstract
Background: despite well-studied safety profile of dabigatran its interactions with genetic polymorphism parameters are poorly understood, especially in patients with moderate chronic kidney disease (CKD). This study was aimed to evaluate relationships between CES1 and ABCB1 polymorphism, dabigatran trough plasma concentration (DTPC) and bleeding events in patients with AF and CKD.
Methods: patients with atrial fibrillation (AF) and stage 3 CKD treated with dabigatran 110mg or 150 mg have been included in the study. Real-time PCR was used to evaluate single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs1045642, rs4148738) and CES1 gene (rs2244613). A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index.
Results: a total of 60 patients, aged 51–89 years (median age 76 years) were evaluated. Compared with patients given 150 mg twice a day, those given 110 mg twice a day were older (79 vs 67.5, p < 0.0001) and had lower creatinine clearance (CrCl) (50.5 vs 60.5 mL/min/1.73 m2, p = 0.015). We found C/D values to have high interindividual variability (mean 365.9 ± 290.4 μg/ml: mg/day, range 23.64-1452.73). Individuals with CKD 3B had higher concentration of dabigatran compared with those with 3A stage (488.7 ± 232.3 vs 332 ± 297.8 μg/ml : mg/day, p = 0.02). Consequently, there also was negative correlation of C/D with CrCl (r = -0.4, p = 0.0015). Evaluated SNPs (rs1045642, rs4148738, and rs2244613) did not affect C/D values (H test p > 0.05).
Conclusions: C/D values were significantly higher in patients with CKD 3B stage and those treated with dabigatran 110 mg. There was no influence of aforementioned SNPs on dabigatran trough concentrations and clinical outcomes.
About the Authors
A. I. Skripka
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Alena I. Skripka, student, Chair of Faculty Therapy N1
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
P. O. Bochkov
Russian Medical Academy of Postgraduate Education; Research Institute of Molecular and Personalized Medicine of the Russian Medical Academy of Continuous Professional Education
Russian Federation
Russian Federation
Pavel O. Bochkov, Cand. of Sci. (Bio), Senior Researcher, Department of Personalized Medicine, Research Center
2/1, b. 1, Barrikadnaya St., Moscow, 125993, Russia
7/2, 2nd Botkinsky P., Moscow, 125284, Russia
K. A. Akmalova
Russian Medical Academy of Postgraduate Education; Research Institute of Molecular and Personalized Medicine of the Russian Medical Academy of Continuous Professional Education
Russian Federation
Kristina A. Akmalova, Researcher, Department of Personalized Medicine
Russian Federation
Kristina A. Akmalova, Researcher, Department of Personalized Medicine
2/1, b. 1, Barrikadnaya St., Moscow, 125993, Russia
7/2, 2nd Botkinsky P., Moscow, 125284, Russia
R. V. Shevchenko
Russian Medical Academy of Postgraduate Education; Research Institute of Molecular and Personalized Medicine of the Russian Medical Academy of Continuous Professional Education
Russian Federation
Roman V. Shevchenko, Cand. of Sci. (Med.), Researcher, Department of Personalized Medicine
Russian Federation
Roman V. Shevchenko, Cand. of Sci. (Med.), Researcher, Department of Personalized Medicine
2/1, b. 1, Barrikadnaya St., Moscow, 125993, Russia
7/2, 2nd Botkinsky P., Moscow, 125284, Russia
P. M. Krupenin
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Pavel M. Krupenin, Post-Graduate Student, Сhair of neurology and neurosurgery
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
V. V. Kogay
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Veronika V. Kogay, 6-th Year Student
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
A. I. Listratov
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Alexander I. Listratov, 6-th Year Student
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
A. S. Krainyaya
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Arina S. Krainyaya, 6-th Year Student
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
D. A. Napalkov
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Dmitriy A. Napalkov, Dr. of Sci. (Med.), Professor, Associate Professor of Chair for Faculty Therapy No. 1
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
O. S. Gurinovich
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Olga S. Gurinovich, 6-th Year Student, Federal State Autonomous Educational Institution of Higher Education
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
A. A. Sokolova
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Anastasiya A. Sokolova, Cand. of Sci. (Med.), Associate Professor, Chair for Faculty Therapy No. 1
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
V. V. Fomin
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Viktor V. Fomin, Dr. of Sci. (Med.), Professor, Corr. Member of RAS, Chair for Faculty Therapy N1
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
D. A. Sychev
First Moscow State Medical University named after I.M. Sechenov (Sechenov University)
Russian Federation
Russian Federation
Dmitriy A. Sychev, Dr. of Sci. (Med.), Professor, Corr. Member of RAS, Chair for Faculty Therapy N1
8, p. 2, Trubetskaya Street, Moscow, 119991, Russia
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For citations:
Skripka AI, Bochkov PO, Akmalova KA, Shevchenko RV, Krupenin PM, Kogay VV, Listratov AI, Krainyaya AS, Napalkov DA, Gurinovich OS, Sokolova AA, Fomin VV, Sychev DA. Safety of dabigatran in patients with atrial fibrillation and chronic kidney disease: pharmacokinetic and pharmacogenetic aspects. Meditsinskiy sovet = Medical Council. 2019;(21):65-73. (In Russ.) https://doi.org/10.21518/2079-701X-2019-21-65-73
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