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

ABSTRACT

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.

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.

Key Words::

• Acenocoumarol
• Aliskiren
• Antihypertensive
• Bioavailability
• Drug–drug interactions
• Prothrombin time

Acknowledgments

Declaration of interest: This work was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. All authors are employees of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA and are eligible for Novartis stock and stock options. The authors participated in the design of the study and in the writing of the study protocol, approved the final protocol, participated in the collection, analysis, and interpretation of data, in the writing of the manuscript and approved the final manuscript. The authors take full responsibility for the content of the paper but thank Dr Ann Taylor (Oxford PharmaGenesisTM Ltd) for assistance in collating the comments of all the authors and editing the final manuscript.

Notes

* These results were presented in a Poster format at the 109th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, 2–5 April 2008, Orlando, FL, USA

* Sintrom is a registered trademark of Novartis Farma SPA, Torre Annunziata, Italy

* Innovin is a registered trademark of Dade Behring Canada Inc., Mississauga ON, Canada