title: Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study.
abstract: Riociguat (BAY 63-2521) and warfarin are likely to be used concomitantly to treat pulmonary hypertension. The aim of this double-blind, crossover, clinical pharmacological study in 30 healthy volunteers was to investigate potential pharmacodynamic and pharmacokinetic interactions between the 2 drugs. Healthy volunteers took 2.5 mg of oral riociguat or matching placebo 3 times daily for 10 days. A single oral dose of warfarin sodium (25 mg) was given 21 days before the study and on the seventh day of riociguat/placebo treatment. Twenty-one participants valid for safety analysis reported 89 treatment-emergent adverse events, all of mild or moderate severity. No serious adverse events occurred. The most frequently reported treatment-emergent adverse events considered to be drug-related were dyspepsia, headache, flatulence, nausea, and vomiting. Twenty-two participants were valid for pharmacodynamic/pharmaco-kinetic analysis. Riociguat (2.5 mg 3 times daily) had no pharmacodynamic interaction with warfarin. Steady-state plasma levels of riociguat did not affect prothrombin time, factor VII clotting activity, or the pharmacokinetics of warfarin. The single dose of warfarin led to a slight decrease (16%) in maximum concentration of riociguat in plasma, which is not likely to be clinically relevant. Clinical studies will confirm the finding here that combined use of riociguat with warfarin will not require dose adaptation.
authors.affiliation: Clinical Pharmacology, Bayer HealthCare AG, Pharma Research Center, Aprather Weg 18a, 42113 Wuppertal, Germany. reiner.frey@bayerhealthcare.com
authors.forename: Reiner
authors.initials: R
authors.lastname: Frey
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mück
authors.forename: Nina
authors.initials: N
authors.lastname: Kirschbaum
authors.forename: Jörn
authors.initials: J
authors.lastname: Krätzschmar
authors.forename: Gerrit
authors.initials: G
authors.lastname: Weimann
authors.forename: Georg
authors.initials: G
authors.lastname: Wensing
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D006162:Guanylate Cyclase; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000071756:Soluble Guanylyl Cyclase; D013237:Stereoisomerism; D014859:Warfarin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D011720:Pyrazoles; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014859:Warfarin; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C542595:riociguat