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

Effects of age and gender on the pharmacokinetics of the soluble guanylate cyclase stimulator riociguat

BMC Pharmacology and Toxicology volume 14, Article number: P23 (2013) Cite this article

  • 1417 Accesses

  • 3 Citations

Background

Pulmonary hypertension is a disabling disease associated with high mortality [1, 2]. Riociguat (under review for the treatment of pulmonary hypertension) stimulates soluble guanylate cyclase, which plays an important role in the regulation of cardiovascular tone and remodelling [3–9]. We investigated the potential effects of age and gender on the pharmacokinetics of riociguat and its primary metabolite M1 (BAY 60-4552). Safety and tolerability of riociguat were also assessed.

Methods

This placebo-controlled, double-blind, single-centre study followed good clinical practice guidelines. Healthy volunteers were randomized into four groups according to age (young, 18–45 years; elderly, 64.5–80 years) and gender: young male (YM), elderly male (EM), young female (YF), elderly female (EF). All participants received a single oral tablet of riociguat 2.5 mg or placebo. Dense sampling was performed for pharmacokinetics.

Results

Forty-seven participants provided data for pharmacokinetic and safety analyses. Nine participants in each group received riociguat; three participants in each of the YM, EM and EF groups and two participants in the YF group received placebo.

Age: the mean maximum concentration of riociguat in plasma (Cmax) did not vary markedly between age groups (Figure 1). However, mean renal clearance was decreased in the elderly, and exposure (area under the plasma concentration–time curve [AUC]) to riociguat was approximately 40% higher in the elderly than in the young (p > 0.05) (Tables 1 & 2). When normalized for body weight, the riociguat exposure (AUCnorm) ratio was reduced; AUCnorm was approximately 30% higher in the elderly than in the young (Tables 1 & 2).

Figure 1
figure1

Mean riociguat plasma concentrations in groups of differing age and gender following administration of a single oral dose of riociguat 2.5 mg.

Full size image
Table 1 Selected pharmacokinetic parameters of riociguat and metabolite M1 (BAY 60-4552) by age and gender following a single oral dose of riociguat 2.5 mg
Full size table
Table 2 Comparison of selected riociguat and M1 pharmacokinetic parameters between different participant groups (ratios and 90% confidence limits)
Full size table

Gender: although riociguat mean Cmax normalized for body weight (Cmax,norm) was significantly greater in women than in men, no difference in exposure was observed between genders (Tables 1 & 2).

Across age groups, pharmacokinetics of M1 followed similar trends to those of riociguat, although differences were less pronounced (Tables 1 & 2). Compared with the combined placebo subgroups, the combined riociguat subgroups demonstrated an expected reduction in mean blood pressure and corresponding elevation of mean heart rate, waning approximately 16 hours post-dose. Three participants in the riociguat subgroups reported drug-related adverse events, one of which (hypotension) was classified as severe. All adverse events had resolved by completion of the study.

Conclusion

Age and gender had modest effects on riociguat and M1 pharmacokinetics, and the safety profile of riociguat was similar across all groups. Thus, no dose adjustment for age or gender is merited.

References

  1. 1.

    D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al: Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991, 115: 343-349. 10.7326/0003-4819-115-5-343.

  2. 2.

    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.

  3. 3.

    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.

  4. 4.

    Schermuly R, Stasch JP, Pullamsetti SS, Middendorff R, Mueller D, Schlüter KD, Dingendorf A, Hackemack S, Kolosionek E, Kaulen C, Dumitrascu R, Weissmann N, Mittendorf J, Klepetko W, Seeger W, Ghofrani HA, Grimminger F: Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008, 32: 881-891. 10.1183/09031936.00114407.

  5. 5.

    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.

  6. 6.

    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.

  7. 7.

    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.

  8. 8.

    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.

  9. 9.

    Hoeper MM, Halank M, Wilkens H, Gunther A, Weimann G, Gebert I, Leuchte H, Behr J: Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial. Eur Respir J. 2013, 41: 853-860. 10.1183/09031936.00213911.

Download references

Acknowledgements

We thank Miguel Zinny, Maryellen Fitzgerald, Arthur LaFluer and Carolyn Maloney of ProMedica Clinical Research Center, Inc., and Christa Rotolo, Pavur Sundaresan and Arthur Mazzu of Bayer HealthCare Pharmaceutical Division for their contributions to the conduct of the study. Writing support was provided by Esther Illman of Oxford PharmaGenesis™ Ltd, and was funded by a research grant from Bayer Pharma AG.

Author information

Affiliations

  1. Clinical Pharmacology, Bayer Pharma AG, Pharma Research Centre, Wuppertal, Germany
    • Reiner Frey
    • , Corina Becker
    •  & Wolfgang Mück
  2. Clinical Pharmacology, Bayer HealthCare Pharmaceuticals, Montville, NJ, USA
    • John Lettieri
  3. Clinical Statistics, Bayer HealthCare Pharmaceuticals, Montville, NJ, USA
    • Andrea Nadel
Authors
  1. Search for Reiner Frey in:
  2. Search for John Lettieri in:
  3. Search for Andrea Nadel in:
  4. Search for Corina Becker in:
  5. Search for Wolfgang Mück 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., Lettieri, J., Nadel, A. et al. Effects of age and gender on the pharmacokinetics of the soluble guanylate cyclase stimulator riociguat. BMC Pharmacol Toxicol 14, P23 (2013). https://doi.org/10.1186/2050-6511-14-S1-P23

Download citation

Keywords

  • Pulmonary Hypertension
  • Young Male
  • Young Female
  • Elderly Male
  • Good Clinical Practice Guideline

BMC Pharmacology and Toxicology

ISSN: 2050-6511

Contact us