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DRUG INTERACTIONS

Significant Pharmacokinetic and Pharmacodynamic Interaction of Warfarin With the NO-Independent sGC Activator HMR1766

Heike Oberwittler, MD, Andreas Hirschfeld-Warneken, Roland Wesch, PhD, Hans Willerich, Lenore Teichert, MSc, Karl-Heinz Lehr, PhD, Reinhard Ding, MD, Walter Emil Haefeli, MD and Gerd Mikus, MD, MSc

From the University of Heidelberg, Heidelberg, Germany (Dr Oberwittler, Mr Hirschfeld-Warneken, Dr Ding, Dr Haefeli, Dr Mikus) and sanofiaventis Deutschland GmbH, Frankfurt, Germany (Dr Wesch, Mr Willerich, Ms Teichert, Dr Lehr). Study site: University of Heidelberg, Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, Heidelberg, Germany.

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.

Key Words: Drug interaction • HMR1766 • NO-independent soluble guanylyl cyclase activator • warfarin • CYP2C9 polymorphism

Address for reprints: Gerd Mikus, MD, University of Heidelberg, Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; e-mail: gerd.mikus{at}med.uni-heidelberg.de.






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