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
Mean riociguat plasma concentrations in groups of differing age and gender following administration of a single oral dose of riociguat 2.5 mg.
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
Parameter
Young female (n = 9)
Elderly female (n = 9)
Young male (n = 9)
Elderly male (n = 9)
Riociguat
AUC, μg·h/L
803 (55)
1145 (36)
750 (58)
1036 (48)
Cmax, μg/L
113 (22)
125 (35)
80.4 (25)
96.7 (32)
AUCnorm, g·h/L
24.8 (57)
32.6 (45)
26.5 (55)
32.8 (50)
Cmax,norm, g/L
3.48 (20)
3.56 (36)
2.84 (23)
3.06 (22)
t½, h
8.97 (51)
11.8 (31)
8.10 (39)
12.2 (62)
CLR, L/ha
0.320 (28)
0.223 (33)
0.389 (37)
0.287 (28)
M1
AUC, μg·h/L
640 (26)
651 (38)
476 (20)
687 (44)
Cmax, μg/L
28.1 (53)
22.4 (52)
14.9 (44)
18.8 (71)
AUCnorm, g·h/L
20.5 (26)
19.2 (30)
17.4 (28)
22.5 (35)
Cmax,norm, g/L
0.899 (51)
0.661 (42)
0.544 (51)
0.615 (65)
t½, h
16.0 (34)
16.7 (21)
14.9 (28)
21.3 (33)
CLR, L/ha
0.824 (32)
0.487 (36)
0.718 (39)
0.573 (44)
aArithmetic mean (percentage coefficient of variation). All other parameters are expressed as 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; Cmax, maximum concentration in plasma; Cmax,norm, Cmax divided by dose per kilogram of body weight; t½, terminal elimination half-life; CLR, renal clearance.
Table 2
Comparison of selected riociguat and M1 pharmacokinetic parameters between different participant groups (ratios and 90% confidence limits)
Parameter
Elderly vs young (n = 18 per group)
Female vs male (n = 18 per group)
Riociguat
AUC
1.40 (1.06–1.86)
1.09 (0.82–1.44)
Cmax
1.16 (0.98–1.36)
1.35 (1.14–1.59)*
AUCnorm
1.28 (0.95–1.71)
0.97 (0.72–1.30)
Cmax,norm
1.05 (0.91–1.22)
1.20 (1.03–1.38)*
t½
1.41 (1.08–1.84)*
1.04 (0.79–1.35)
M1
AUC
1.21 (1.00–1.46)
1.13 (0.94–1.36)
Cmax
1.00 (0.73–1.38)
1.50 (1.09–2.05)*
AUCnorm
1.10 (0.93–1.30)
1.00 (0.85–1.19)
Cmax,norm
0.91 (0.68–1.23)
1.33 (0.99–1.79)
t½
1.22 (1.04–1.44)*
0.92 (0.78–1.08)
*p < 0.05 for ratio = 1.
AUC, area under the plasma concentration–time curve from time 0 to infinity; AUCnorm, AUC divided by dose per kilogram of body weight; Cmax, maximum concentration in plasma; Cmax,norm, Cmax divided by dose per kilogram of body weight; t½, terminal elimination half-life.
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.
Declarations
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.
Authors’ Affiliations
(1)
Clinical Pharmacology, Bayer Pharma AG, Pharma Research Centre
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