Skip to main content

Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Volume 14 Supplement 1

6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Pharmacokinetics of the soluble guanylate cyclase stimulator riociguat in individuals with renal impairment

BMC Pharmacology and Toxicology volume 14, Article number: P22 (2013) Cite this article

  • 1210 Accesses

  • 5 Citations

Background

Riociguat is the first oral, soluble guanylate cyclase stimulator under review for the treatment of pulmonary hypertension (PH), a progressive, ultimately fatal disease [1–7]. This pooled analysis of two studies evaluated the pharmacokinetics of riociguat and its metabolite M1 (BAY 60-4552) in individuals with and without renal impairment. The safety and tolerability of riociguat were also assessed.

Methods

Two non-randomized, non-blinded, observational studies with group stratification were conducted in a single centre in Germany, following Good Clinical Practice and relevant industry guidelines [8, 9]. Participants were assigned to one of four renal function groups according to their creatinine clearance (CLCR): group 1, CLCR > 80 mL/min; group 2, CLCR 50–80 mL/min; group 3, CLCR 30–49 mL/min; group 4, CLCR < 30 mL/min. In the first study, individuals in group 4 received riociguat 0.5 mg; all other participants in both studies received riociguat 1 mg (single tablet doses). Pharmacokinetic parameters were assessed using dense sampling.

Results

Sixty-three participants (40 men and 23 women; mean age, 61.3 years [range, 36–78 years]) completed the study and were eligible for pharmacokinetic analysis. Riociguat was rapidly absorbed; median time to reach maximum concentration in plasma (tmax) (Cmax) was 1 hour in all four groups. Mean half-life of total riociguat was longer in groups 2–4 (9.5–11.4 hours) than in group 1 (6.2 hours) (Table 1), and renal clearance of riociguat decreased with decreasing renal function. Mean exposure to total riociguat (area under the concentration–time curve divided by dose per kilogram of body weight [AUCnorm]) was 42.7–104.3% higher in groups 2–4 than in group 1 (Table 1, Figure 1). However, exposure was highly variable in groups 2–4 and the exposure ranges in all groups overlapped (Figure 1). Exposure to riociguat did not increase strictly in parallel with decreasing CLCR. Results for unbound riociguat and M1 were similar to those for total riociguat and M1. No serious or severe adverse events were reported. Headache was the most common drug-related adverse event. No changes in safety or tolerability were detected with decreasing CLCR. Riociguat Cmax and AUC ranges in patients with renal impairment overlapped those previously observed in healthy volunteers and patients with PH [2, 3].

Table 1 Pharmacokinetic parameters of riociguat in healthy participants and in individuals with mild, moderate or severe renal impairment
Full size table
Figure 1
figure1

Box-and-whisker plot of riociguat AUCnorm (kg·h/L) after a single oral dose of riociguat. In the first study, individuals with severe renal impairment (group 4) received riociguat 0.5 mg; all other participants in both studies received riociguat 1 mg . Box, 25–75th percentile; vertical line, 10th–90th percentile; horizontal line, median; more extreme values are plotted as points; individuals eligible for pharmacokinetic analysis, n = 63; AUCnorm, area under the plasma concentration–time curve from time 0 to infinity divided by dose per kilogram of body weight for total riociguat.

Full size image

Conclusion

Exposure to riociguat was higher in individuals with renal impairment (CLCR 15–80 mL/min) than in controls; particular care should be exercised during individual dose titration in patients with renal impairment.

References

  1. 1.

    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.

  2. 2.

    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.

  3. 3.

    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.

  4. 4.

    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.

  5. 5.

    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.

  6. 6.

    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.

  7. 7.

    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.

  8. 8.

    Guidance for Industry. Pharmacokinetics in Patients with Impaired Renal Function - Study Design, Data Analysis, and Impact on Dosing and Labeling [http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072127.pdf].

  9. 9.

    Note for Guidance on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Renal Function [http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003123.pdf].

Download references

Acknowledgements

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.

Author information

Affiliations

  1. Clinical Pharmacology, Bayer Pharma AG, Pharma Research Centre, Wuppertal, Germany
    • Reiner Frey
    • , Corina Becker
    • , Anja Schmidt
    • , Georg Wensing
    •  & Wolfgang Mueck
  2. Global Biostatistics, Bayer Pharma AG, Pharma Research Centre, Wuppertal, Germany
    • Sigrun Unger
Authors
  1. Search for Reiner Frey in:
  2. Search for Corina Becker in:
  3. Search for Sigrun Unger in:
  4. Search for Anja Schmidt in:
  5. Search for Georg Wensing in:
  6. Search for Wolfgang Mueck in:

Corresponding author

Correspondence to Reiner Frey.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Frey, R., Becker, C., Unger, S. et al. Pharmacokinetics of the soluble guanylate cyclase stimulator riociguat in individuals with renal impairment. BMC Pharmacol Toxicol 14, P22 (2013). https://doi.org/10.1186/2050-6511-14-S1-P22

Download citation

Keywords

  • Pulmonary Hypertension
  • Renal Impairment
  • Severe Adverse Event
  • Dose Titration
  • Individual Dose

BMC Pharmacology and Toxicology

ISSN: 2050-6511

Contact us