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% CI 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% CI 0.92, 1.54) and a 9% increase in C(max) (GMR 1.09; 90% CI 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), PT(max), AUC(INR) and INR(max)), with 90% CI within the range 0.97-1.05.


CONCLUSIONS
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.
Huang
H-L A
HL
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Vaidyanathan
S
S
Yeh
C-M
CM
Bizot
M-N
MN
Dieterich
H A
HA
Dole
W P
WP
Howard
D
D
D000074:Acenocoumarol / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D049669:History, 16th Century; D006801:Humans; D008297:Male; D013056:Spectrophotometry, Ultraviolet; D000092502:Renin Inhibitors
D000074:Acenocoumarol; D000577:Amides; D000925:Anticoagulants; D005650:Fumarates; D000092502:Renin Inhibitors; C446481:aliskiren