Volume 14 Supplement 1

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

Open Access

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

  • Reiner Frey1Email author,
  • Corina Becker1,
  • Sigrun Unger2,
  • Anja Schmidt1,
  • Georg Wensing1 and
  • Wolfgang Mueck1
BMC Pharmacology and Toxicology201314(Suppl 1):P21

DOI: 10.1186/2050-6511-14-S1-P21

Published: 29 August 2013

Background

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 [17]. 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.

Methods

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.

Results

Sixty-four participants (42 men and 22 women; mean age, 55.1 years [range, 35–72 years]) received riociguat and completed the study according to protocol. Owing to the rapid absorption of riociguat (median time to reach maximum concentration in plasma [Cmax], ≤ 1.5 hours in all groups), mean dose- and body-weight-normalized Cmax values for total riociguat were similar in all groups (Table 1). Mean half-life of total riociguat was longer in the Child–Pugh B group than in the Child–Pugh A group and the controls (Table 1). Exposure (dose- and body-weight-normalized area under the plasma concentration–time curve [AUCnorm]) to total riociguat was elevated in Child–Pugh B but not Child-Pugh A individuals compared with controls (Table 1, Figure 1). Antagonizing effects – reduced rate of formation and impaired M1 elimination – led to relatively small differences in overall exposure to M1 in the Child–Pugh A and B groups and their controls. Results for unbound riociguat and M1 were similar to those for total riociguat and M1. No serious or severe adverse events were reported. The most common drug-related adverse event was headache. There was no difference in safety or tolerability between study groups. Riociguat AUC and Cmax ranges in patients with hepatic impairment overlapped those previously observed in healthy volunteers and patients with PH [2, 3].
Table 1

Pharmacokinetic parameters of riociguat in plasma following a single oral dose of riociguat 1 mg

Parameter

Child–Pugh A (n = 16)

Child–Pugh B (n = 16)

Control A (n = 16)

Control B (n = 16)

AUC, μg·h/L

371.0 (74)

458.9 (62)

349.9 (67)

300.9 (92)

Cmax, μg/L

42.67 (37)

43.27 (39)

42.67 (23)

38.68 (30)

AUCnorm, kg·h/L

30.9 (75)

36.6 (65)

29.1 (67)

23.9 (94)

Cmax,norm, kg/L

3.56 (33)

3.45 (26)

3.55 (20)

3.07 (23)

t½, h

9.19 (53)

13.7 (50)

9.02 (63)

7.54 (86)

Values are geometric means (percentage coefficient of variation). AUC, area under the plasma concentration–time curve from time 0 to infinity; AUCnorm, AUC divided by dose per kilogram of body weight for total riociguat; Cmax, maximum concentration in plasma; Cmax,norm, Cmax divided by dose per kilogram of body weight for total riociguat; t½, terminal elimination half-life for total riociguat.

Figure 1

Box-and-whisker plot of riociguat AUCnorm (kg·h/L) after a single oral dose of riociguat 1 mg. Box, 25th–75th percentile; vertical line, 10th–90th percentile; horizontal line, median; more extreme values are plotted as points; individuals eligible for pharmacokinetic analysis, n = 64; AUCnorm, area under the plasma concentration–time curve from time 0 to infinity divided by dose per kilogram of body weight for total riociguat.

Conclusion

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.

Declarations

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.

Authors’ Affiliations

(1)
Clinical Pharmacology, Bayer Pharma AG, Pharma Research Centre
(2)
Global Biostatistics, Bayer Pharma AG, Pharma Research Centre

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Copyright

© Frey et al; licensee BioMed Central Ltd. 2013

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.

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