Effect of pitavastatin vs. rosuvastatin on international normalized ratio in healthy volunteers on steady-state warfarin

Abstract

Objective:

Statins have been shown to impact international normalized ratio (INR) when coadministered with warfarin. The aim of this study was to assess the effect of pitavastatin compared with rosuvastatin on steady-state pharmacodynamics (PD) of warfarin by measuring INR in healthy adult subjects.

Methods:

Subjects received oral doses of warfarin 5 mg once daily on days 1 through 3. The dose was titrated on days 4 through 9 to reach a steady-state INR of 1.5 to 2.2. Warfarin was continued on days 10 through 21 and pitavastatin 4 mg or rosuvastatin 40 mg was administered once daily on days 14 through 22. After a 14-day washout period, the process was repeated with the alternate statin.

Study number:

NK-104-4.03US.

Results:

For pitavastatin, mean INR changed from 1.73 ± 0.18 (n = 42) on day 14 before starting statin dosing, to 1.78 ± 0.29 (n = 42) on day 22 at treatment end; the difference in INR was not significant (p = 0.219). For rosuvastatin, mean INR increased significantly from 1.74 ± 0.20 (n = 43) at baseline to 1.90 ± 0.30 (n = 43) at treatment end (p < 0.001). Rosuvastatin caused a significantly greater increase in INR than pitavastatin (p < 0.001).

Conclusion:

Steady-state INR during warfarin treatment did not change significantly when pitavastatin 4 mg was added to the regimen, while a significant increase was observed when rosuvastatin 40 mg was added. The effect of rosuvastatin on INR was significantly larger than the effect of pitavastatin. This study is limited because it was done in healthy volunteers. Further studies in patient populations are needed to better understand the clinical significance of the results.

Keywords::

• INR
• Pitavastatin
• Rosuvastatin
• Warfarin

Transparency

Declaration of funding

This study was sponsored by Eli Lilly and Company, Indianapolis, IN, USA; the Kowa Research Institute, Inc., Morrisville, NC, USA; and Kowa Pharmaceuticals America, Inc., Montgomery, AL, USA.

Declaration of financial/other relationships

C.Y.Y. is an employee and minor stockholder of Eli Lilly. S.E.C. is an employee of the Kowa Research Institute. B.Z. is a shareholder in Eli Lilly. M.P.K. is an employee and shareholder in Eli Lilly, which co-markets Livalo. D.S.S. is an employee of and owns stock in Eli Lilly. T.L.H. has disclosed that he has no significant financial interests in any commercial companies related to this study or article. R.E.M. is an employee of the Kowa Research Institute. C.A.S. is an employee of the Kowa Pharmaceuticals America.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

The authors would like to acknowledge Dr. Malcolm Mitchell, Dr. Mark Effron, and Dr. LeRoy LeNarz for their input in study design, and Maryann Weller of i3 Statprobe for assistance in writing this manuscript.