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Pharmacokinetics of the soluble guanylate cyclase stimulator riociguat in individuals with hepatic impairment
© Frey et al; licensee BioMed Central Ltd. 2013
- Published: 29 August 2013
- Pulmonary Hypertension
- Liver Cirrhosis
- Hepatic Impairment
- Oral Tablet
- Moderate Hepatic Impairment
Riociguat is the first oral, soluble guanylate cyclase stimulator currently under review for the treatment of pulmonary hypertension (PH), a progressive disease with high mortality [1–7]. The present pooled analysis assessed the pharmacokinetics of riociguat and its metabolite M1 (BAY 60-4552) in individuals with hepatic impairment (Child–Pugh A or B) and healthy controls. The safety and tolerability of riociguat were evaluated.
Two non-randomized, non-blinded, observational studies with group stratification were included in the analysis. The studies were conducted in a single centre in Germany, in accordance with Good Clinical Practice and industry guidelines [8, 9]. Individuals with liver cirrhosis (Child–Pugh A, n = 16; Child–Pugh B, n = 16) and 32 healthy age-, weight- and sex-matched volunteers received a single oral tablet dose of riociguat 1 mg. Dense sampling was performed for pharmacokinetic parameters.
Pharmacokinetic parameters of riociguat in plasma following a single oral dose of riociguat 1 mg
Child–Pugh A (n = 16)
Child–Pugh B (n = 16)
Control A (n = 16)
Control B (n = 16)
Child–Pugh A individuals had similar plasma riociguat concentrations to controls. Child–Pugh B individuals had a higher exposure to riociguat than those in the other groups; particular care should be exercised during individual dose titration in patients with moderate hepatic impairment.
The studies were funded by Bayer Pharma AG, Wuppertal, Germany, and performed by Atef Halabi, Clinical Trial Director, CRS Clinical Research Services Kiel GmbH, Lornsenstrasse 7, 24105 Kiel, Germany.
- Stasch JP, Pacher P, Evgenov OV: Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011, 123: 2263-2273. 10.1161/CIRCULATIONAHA.110.981738.PubMed CentralView ArticlePubMedGoogle Scholar
- Frey R, Mück W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G: Single-dose pharmacokinetics, tolerability and safety of the soluble guanylate cyclase stimulator BAY 63-2521; an ascending-dose study in healthy male volunteers. J Clin Pharmacol. 2008, 48: 926-934. 10.1177/0091270008319793.View ArticlePubMedGoogle Scholar
- Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bölkow D, Weissmann N, Mück W, Unger S, Wensing G, et al: First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009, 33: 785-792. 10.1183/09031936.00039808.View ArticlePubMedGoogle Scholar
- Ghofrani HA, Hoeper MM, Halank M, Meyer FJ, Staehler G, Behr J, Ewert R, Weimann G, Grimminger F: Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J. 2010, 36: 792-799. 10.1183/09031936.00182909.View ArticlePubMedGoogle Scholar
- Ghofrani H, Galie N, Grimminger F, Humbert M, Keogh A, Langleben D, Kilama MO, Neuser D, Rubin L: Riociguat for the treatment of pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study (PATENT-1). Chest. 2012, 142: 1027A-10.1378/chest.1462799.View ArticleGoogle Scholar
- Ghofrani H, Grimminger F, Hoeper M, Kim N, Mayer E, Neuser D, Pena J, Simonneau G, Wilkins M: Riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension: a randomized, double-blind, placebo-controlled study (CHEST-1). Chest. 2012, 142: 1023A-10.1378/chest.1462924.View ArticleGoogle Scholar
- Hurdman J, Condliffe R, Elliot CA, Davies C, Hill C, Wild JM, Capener D, Sephton P, Hamilton N, Armstrong IJ, Billings C, Lawrie A, Sabroe I, Akil M, O'Toole L, Kiely DG: Aspire Registry: assessing the spectrum of pulmonary hypertension identified at a referral centre. Eur Respir J. 2012, 39: 945-955. 10.1183/09031936.00078411.View ArticlePubMedGoogle Scholar
- Guidance for industry. Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, & impact on dosing and labeling [http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf].
- Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function [http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003122.pdf].
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