title: Significant pharmacokinetic and pharmacodynamic interaction of warfarin with the NO-independent sGC activator HMR1766.
abstract: 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.
authors.affiliation: University of Heidelberg, Heidelberg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Oberwittler
authors.forename: Andreas
authors.initials: A
authors.lastname: Hirschfeld-Warneken
authors.forename: Roland
authors.initials: R
authors.lastname: Wesch
authors.forename: Hans
authors.initials: H
authors.lastname: Willerich
authors.forename: Lenore
authors.initials: L
authors.lastname: Teichert
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Lehr
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ding
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D004311:Double-Blind Method; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D008297:Male; D009391:Nephelometry and Turbidimetry; D011517:Prothrombin Time; D013449:Sulfonamides / Q000097:blood / Q000378:metabolism*; D013607:Tablets; D013997:Time Factors; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D062367:ortho-Aminobenzoates / Q000097:blood / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; D013449:Sulfonamides; D013607:Tablets; D062367:ortho-Aminobenzoates; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D006162:Guanylate Cyclase; C515616:5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide