Influence of ABCB1 Polymorphisms on Plasma Concentrations of New Oral Anticoagulants in Case of Serious Adverse Events
Condition: Anticoagulants; Thromboembolism; Hemorrhage
MeSH terms: Thromboembolism; Hemorrhage
Study type: Interventional

Summary: 
      Vitamin K antagonists were hampered by several disadvantages, such as the need for frequent
      monitoring. In this context, new oral anticoagulants (NOACs) have been developed and are now
      available on the market. These NOACs, like all anticoagulant drugs, continue to be associated
      with an increased risk of bleeding. In addition, the lack of antidote and the absence of
      valid data regarding biological monitoring can pose problems in case of overdose or when
      emergency surgery is required. Studies investigating the pharmacokinetic properties of
      rivaroxaban and dabigatran, two NOACs now approved for the market, have shown high
      variability between individuals, with coefficients of variation of up to 60% for some
      pharmacokinetic parameters in patients treated after orthopaedic surgery. The relation
      between plasma concentrations of NOAC and bleeding risk has been clearly established in
      clinical trials.

      Dabigtran, rivaroxaban and apixaban are known substrates of P-glycoprotein (Pgp). Pgp
      activity can be affected by pharmacological inducing or inhibiting agents. This can lead to a
      significant change in the pharmacokinetics of NOACs, with a decrease or increase
      (respectively) in the level of intestinal absorption, leading to respectively reduced or
      increased plasma concentrations of the drug. Furthermore, there exist genetic mutations of
      Pgp, presenting in particular a lower level of activity than the non-mutated protein. We
      hypothesized that the polymorphisms (mutations) of the ABCB1 gene that codes for Pgp could
      influence plasma concentrations of dabigatran, rivaroxaban and apixaban, and consequently,
      impact on the concentration of NOACs and as a corollary, on the bleeding and thromboembolic
      risk of patients treated with these molecules.

      The main objective of this study is to study the relation between polymorphisms of the ABCB1
      gene that codes for Pgp and plasma concentrations of NOACs in patients treated for a
      hemorrhagic or thromboembolic complication occurring under NOAC therapy.

      Secondary objectives are to evaluate the distribution of ABCB1 polymorphisms among the
      various hemorrhagic risk factors, and to compare the frequency of the polymorphism in
      patients from the study population vs the general population.
    


Intervention name(s): Measurement of Plasma Concentrations of NOACs; Identification of ABCB1 polymorphisms coding for P-gp
Intervention type(s): Other; Genetic
Intervention description(s): Plasma concentrations of dabigatran, rivaroxaban or apixaban will be measured using High Performance Liquid Chromatography (HPLC) coupled with tandem mass spectrometry (MS/MS). Blood samples will be taken in an EDTA tube and rapidly centrifugated. Plasma will be aliquoted and frozen at minus 80 degrees Celsius for later analysis.; To investigate the existence of a relation between polymorphisms of ABCB1 and plasma concentrations of new oral anticoagulants, the SNaPshot® Multiplex System will be used enabling multiplexing of SNPs (single nucleotide polymorphisms) of the ABCB1 gene (namely rs4148738, rs2235046, rs1128503, rs10276036, rs1202169, rs1202168, rs1202167).
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: polymorphism; ABCB1; P-glycoprotein; oral anticoagulant; dabigatran; apixaban; rivaroxaban; hemorrhagic complication; thrombo-embolism; serious adverse event