Oral bioavailability of dabigatran etexilate (Pradaxa®) after co-medication with verapamil in healthy subjects

Aim To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE). Method In this two part multiple crossover trial in 40 healthy subjects, DE 150mg was given alone or with verapamil at different doses, duration of treatment (single vs. multiple dosing), formulations, and timings (before, concurrently or after DE). Primary pharmacokinetic endpoints were determined from concentrations of total dabigatran (unconjugated plus conjugated). Pharmacodynamic endpoints were determined from clotting time. Results The greatest effect was observed with single dose verapamil 120mg immediate release given 1h before single dose DE. Geometric mean area under the plasma concentration curve [AUC(0,)] and maximum analyte concentration in the plasma (Cmax) were increased by 143% [90% confidence interval (CI) 91, 208] and 179% (90% CI 115, 262), respectively. The effect was reduced to a 71% and 91% increase in AUC and Cmax, respectively, when DE was administered with verapamil 240mg extended release. After multiple verapamil dosing, DE AUC(0,) and Cmax increases were 54% and 63%, respectively. However, DE given 2h before verapamil increased DE AUC(0,) and Cmax by <20%. With regard to clotting prolongation, the dabigatran plasma concentrationeffect relationship was generally not affected by the co-administration of verapamil. Concomitant administration of DE and verapamil did not reveal any unexpected safety findings. Conclusion Verapamil increased DE bioavailability, likely due to inhibition of P-glycoprotein. Our results suggest that an interaction between verapamil and DE can be minimized if DE is administered 2h prior to verapamil.