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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: Oberwittler, Heike (Author) , Hirschfeld-Warneken, Andreas (Author) , Wesch, Roland (Author) , Willerich, Hans (Author) , Teichert, Lenore (Author) , Lehr, Karl-Heinz (Author) , Ding, Reinhard (Author) , Haefeli, Walter E. (Author) , Mikus, Gerd (Author)
Format: Article (Journal)
Language:English
Published: 2007
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
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Summary: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.
Item Description:Published: 07 March 2013
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Physical Description:Online Resource
ISSN:1552-4604
DOI:https://doi.org/10.1177/0091270006294540

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