Significant pharmacokinetic and pharmacodynamic interaction of warfarin with the NO-independent sGC activator HMR1766
HMR1766 is a new nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC) in development for the treatment of cardiovascular diseases and chronic heart failure. A significant fraction of patients to be treated with HMR1766 is expected to be maintained on warfarin. Because HMR1766 is...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2007
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| In: |
Journal of clinical pharmacology
Year: 2007, Volume: 47, Issue: 1, Pages: 70-77 |
| ISSN: | 1552-4604 |
| DOI: | https://doi.org/10.1177/0091270006294540 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/https://doi.org/10.1177/0091270006294540 Verlag, lizenzpflichtig, Volltext: https://accp1.onlinelibrary.wiley.com/doi/abs/10.1177/0091270006294540 
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| Author Notes: | Heike Oberwittler, Andreas Hirschfeld‐Warneken, Roland Wesch, Hans Willerich, Lenore Teichert, Karl-Heinz Lehr, Reinhard Ding, Walter Emil Haefeli, and Gerd Mikus |
MARC
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| 245 | 1 | 0 | |a Significant pharmacokinetic and pharmacodynamic interaction of warfarin with the NO-independent sGC activator HMR1766 |c Heike Oberwittler, Andreas Hirschfeld‐Warneken, Roland Wesch, Hans Willerich, Lenore Teichert, Karl-Heinz Lehr, Reinhard Ding, Walter Emil Haefeli, and Gerd Mikus |
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| 520 | |a HMR1766 is a new nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC) in development for the treatment of cardiovascular diseases and chronic heart failure. A significant fraction of patients to be treated with HMR1766 is expected to be maintained on warfarin. Because HMR1766 is an inhibitor and warfarin a substrate of CYP2C9, the authors studied whether warfarin pharmacokinetics and pharmacodynamics are influenced by HMR1766. Eighteen healthy males were to receive a single oral dose of 20 mg warfarin each under steady-state conditions of HMR1766 or placebo. Plasma concentrations of HMR1766, (R)- and (S)-warfarin, and its 7-hydroxy-metabolites were determined using high-performance liquid chromatography and prothrombin time, and the international standardized ratio was determined by the nephelometric method. (S)-Warfarin AUCinf and t1/2 were 106 471 h·μg/L and 82.92 hours versus 33 148 h·μg/L under HMR1766 and 31.72 hours under placebo, and the maximum decrease in prothrombin time values after warfarin dosing was 58.75% versus 39.94%. These data demonstrate a CYP2C9-mediated pharmacokinetic interaction with pharmacodynamic, clinically relevant consequences, which might require warfarin dose adjustment. | ||
| 650 | 4 | |a CYP2C9 polymorphism | |
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| 650 | 4 | |a warfarin | |
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