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 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.