title: Pharmacokinetics of the soluble guanylate cyclase activator cinaciguat in individuals with hepatic impairment.
abstract: Cinaciguat is intended for use in patients with acute decompensated heart failure. The drug is eliminated predominantly via the liver and, therefore, the potential impact of hepatic impairment on cinaciguat pharmacokinetics needs to be determined. This nonrandomized, open-label, observational study investigated the pharmacokinetics of cinaciguat in individuals with mild (Child-Pugh A; n = 8) or moderate (Child-Pugh B; n = 8) hepatic impairment and matched healthy volunteers (n = 16). An exploratory analysis of pharmacodynamic parameters was also conducted. Individuals with mild hepatic impairment and their controls received a single (4-hour) intravenous infusion of 100 µg/h cinaciguat, whereas individuals with moderate hepatic impairment and their controls received 50 µg/h. Cinaciguat was well tolerated and had a favorable safety profile. The most frequent treatment-emergent adverse events were headache (4 participants) and spontaneous penile erection (2 participants). In individuals with mild hepatic impairment, only minor increases in plasma cinaciguat concentrations and no significant differences in pharmacodynamic parameters were observed, compared with controls. Individuals with moderate hepatic impairment had a substantially higher cinaciguat exposure than controls. This higher exposure was associated with more pronounced vasodilatation. This study demonstrates that in individuals with mild hepatic impairment, individual dose adaptation may not be required.
authors.affiliation: Clinical Pharmacology, Bayer HealthCare AG, Pharma Research Center, Aprather Weg 18a, 42113 Wuppertal, Germany. reiner.frey@bayer.com
authors.forename: Reiner
authors.initials: R
authors.lastname: Frey
authors.forename: Christian
authors.initials: C
authors.lastname: Scheerans
authors.forename: Martin
authors.initials: M
authors.lastname: Blunck
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mück
authors.forename: Mark Jean
authors.initials: MJ
authors.lastname: Gnoth
authors.forename: Sigrun
authors.initials: S
authors.lastname: Unger
authors.forename: Anja
authors.initials: A
authors.lastname: Schmidt
authors.forename: Georg
authors.initials: G
authors.lastname: Wensing
mesh_terms: D000328:Adult; D000368:Aged; D001565:Benzoates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000097:blood; D005260:Female; D006162:Guanylate Cyclase; D057809:HEK293 Cells; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008103:Liver Cirrhosis / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D000071756:Soluble Guanylyl Cyclase
chemical_list: D001565:Benzoates; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D018160:Receptors, Cytoplasmic and Nuclear; C503999:SLCO1B1 protein, human; C480588:BAY 58-2667; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP