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 AUC(inf) and t(1/2) were 106,471 h x microg/L and 82.92 hours versus 33,148 h x microg/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.