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...
Enregistré dans:
| Auteurs principaux: | , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Langue: | anglais |
| Publié: |
2007
|
| In: |
Journal of clinical pharmacology
Year: 2007, Volume: 47, Numéro: 1, Pages: 70-77 |
| ISSN: | 1552-4604 |
| DOI: | https://doi.org/10.1177/0091270006294540 |
| Accès en ligne: | 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 
|
| Notes sur l'auteur: | Heike Oberwittler, Andreas Hirschfeld‐Warneken, Roland Wesch, Hans Willerich, Lenore Teichert, Karl-Heinz Lehr, Reinhard Ding, Walter Emil Haefeli, and Gerd Mikus |
| Résumé: | 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. |
|---|---|
| Description: | Published: 07 March 2013 Elektronische Reproduktion der Druck-Ausgabe Gesehen am 12.05.2021 |
| Description matérielle: | Online Resource |
| ISSN: | 1552-4604 |
| DOI: | https://doi.org/10.1177/0091270006294540 |