Therapeutic drug monitoring of direct oral anticoagulants (DOAC's)

The development of three oral anticoagulants: Apixaban, Dabigatran and Rivaroxaban seemed to be a big step forward in pharmacotherapy. Fixed dosage and no longer need for tight monitoring of the INR value offer quite an advantage compared to their older counterparts Phenprocoumon and Warfarin. But is there really no need for monitoring? Rivaroxaban and Apixaban are both substrates of CYP3A4 while Dabigatran makes use of P-gp transport. This seems especially critical in psychiatry where polymedication with CYP450-inhibiton and induction is quite common.

We performed protein precipitation with methanol (1:3) for sample preparation. The method was developed using a RP-C18 column. Eluent (A) was methanol and eluent (B) was water with 0.1% formic acid added in each. A gradient run was performed with 0.7 ml/min at 30 °C starting with 90% (B) and gradually changing to (B) 50% over 3.0 min. This condition was held for until minute 4.5 min. Afterwards the gradient change from (B) 50% to (A) 100% till 7.0 min. Detection was achieved via UV-Vis with absorption maxima at 249nm (Rivaroxaban), 280nm (Apixaban), 307nm (Dabigatran) and 340nm (Dabigatran etexilate).

We developed a rapid UHPLC method for simultaneous quantification of all three drugs in human plasma, in presence with common psychiatric drugs, within a 7 minute run. Up to now we measured 11 samples of patients receiving Rivaroxaban showing a large spread of concentrations across the DRR (Dose related reference range).