Effect of aliskiren, an oral direct renin inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers

Objective: Aliskiren is a direct renin inhibitor approved for the treatment of hypertension. This study investigated the effects of aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers. Methods: This two-sequence, two-period, randomized, double-blind crossover study recruited 18 healthy subjects (ages 18-45) to receive either aliskiren 300 mg or placebo once daily on days 1-10 of each treatment period and a single dose of acenocoumarol 10 mg on day 8. Treatment periods were separated by a 10-day washout. Blood samples were taken frequently for determination of steady-state plasma concentrations of aliskiren (LC-MS/MS) and of R(+)- and S(-)-acenocoumarol (HPLC-UV), prothrombin time (PT) and international normalized ratio (INR). Results: Co-administration with aliskiren had no effect on exposure to R(+)-acenocoumarol. Geometric mean ratios (GMR; aliskiren:placebo co-administration) for R(+)-acenocoumarol AUC(0-t) and C-max were 1.08 and 1.04, respectively, with 90% Cl within the range 0.80-1.25. Co-administration of aliskiren resulted in a 19% increase in S(-)-acenocoumarol AUC(0-t) (GMR 1.19; 90% Cl 0.92, 1.54) and a 9% increase in Cm, (GMR 1.09; 90% Cl 0.88, 1.34). The anticoagulant effect of acenocoumarol was not affected by co-administration of aliskiren. Geometric mean ratios were 1.01 for all pharmacodynamic parameters (AUC(PT), PTmax, AUC(INR) and INRmax), with 90% Cl within the range 0.97-1.05. Conclusion: Aliskiren has no clinically relevant effect on the pharmacokinetics or pharmacodynamic effects of a single dose of acenocoumarol in healthy volunteers, hence no dosage adjustment of acenocoumarol is likely to be required during co-administration with aliskiren.