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Article ; Online: In vitro

Jungmann, Natalia A / Lang, Dieter / Saleh, Soundos / Van Der Mey, Dorina / Gerisch, Michael

Expert opinion on drug metabolism & toxicology

2019 Volume 15, Issue 11, Page(s) 975–984

Abstract: ... ...

Abstract	Objectives
MeSH term(s)	Anti-HIV Agents/administration & dosage ; Anti-HIV Agents/pharmacology ; Cytochrome P-450 CYP1A1/antagonists & inhibitors ; Cytochrome P-450 CYP1A1/metabolism ; Cytochrome P-450 CYP3A/drug effects ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 CYP3A Inhibitors/administration & dosage ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; Drug Interactions ; Enzyme Activators/administration & dosage ; Enzyme Activators/metabolism ; Hepatocytes/enzymology ; Hepatocytes/metabolism ; Humans ; In Vitro Techniques ; Pyrazoles/administration & dosage ; Pyrazoles/metabolism ; Pyrimidines/administration & dosage ; Pyrimidines/metabolism
Chemical Substances	Anti-HIV Agents ; Cytochrome P-450 CYP3A Inhibitors ; Enzyme Activators ; Pyrazoles ; Pyrimidines ; CYP1A1 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; CYP3A4 protein, human (EC 1.14.14.55) ; riociguat (RU3FE2Y4XI)
Language	English
Publishing date	2019-10-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2214462-6
ISSN	1744-7607 ; 1742-5255
ISSN (online)	1744-7607
ISSN	1742-5255
DOI	10.1080/17425255.2019.1681968
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Article ; Online: Population pharmacokinetics of riociguat in a pediatric population (aged ≥ 6 years) with pulmonary arterial hypertension.

Willmann, Stefan / Keller, Andrea Kerstin / Meyer, Michaela / van der Mey, Dorina / Wirsching, Gabriela / Zhang, Yang / Drenth, Henk-Jan / Keunecke, Anne / Vendel, Esmée / Saleh, Soundos

Pediatric pulmonology

2022 Volume 58, Issue 3, Page(s) 908–917

Abstract: Background: The PATENT-CHILD study investigated riociguat in children aged ≥ 6 to <18 years with pulmonary arterial hypertension (PAH) treated with tablets or an oral pediatric suspension based on bodyweight-adjusted dosing of up to 2.5 mg three times ... ...

Abstract	Background: The PATENT-CHILD study investigated riociguat in children aged ≥ 6 to <18 years with pulmonary arterial hypertension (PAH) treated with tablets or an oral pediatric suspension based on bodyweight-adjusted dosing of up to 2.5 mg three times daily. PATENT-CHILD demonstrated an acceptable riociguat safety profile and individual plasma concentrations in pediatric patients were consistent with those in adult patients. Methods: Using the data set from PATENT-CHILD and building on existing population pharmacokinetic (PK) models for riociguat and its major metabolite (M1) in adults with PAH, a coupled riociguat-M1 PK model was developed. The final model developed incorporated a one-compartment model for riociguat, coupled to a one-compartment model for M1, allowing for presystemic formation of M1. It included allometric scaling exponents for bodyweight. Results: Apparent clearance of riociguat was similar in children and adult patients with PAH (median [interquartile range] 2.20 [1.75-3.44] and 2.08 L/h [1.55-2.97]). Factors contributing to lower PK exposure were lower riociguat maintenance dose in PATENT-CHILD, and a higher riociguat clearance in some adolescent patients, compared with adult patients. No effects of formulation, sex, or age on riociguat PK were observed. An exploratory PK/pharmacodynamics analysis found the increase in 6-min walking distance in pediatric patients treated with riociguat was not related to riociguat PK. Conclusions: Body size is the main determinant of PK in growing children, and the model supports clinical data that, for children weighing < 50 kg, a bodyweight-adjusted dose of riociguat should be used to achieve a similar exposure to that observed in adults with PAH.
MeSH term(s)	Adult ; Adolescent ; Humans ; Child ; Pulmonary Arterial Hypertension/drug therapy ; Hypertension, Pulmonary/drug therapy ; Treatment Outcome ; Familial Primary Pulmonary Hypertension/drug therapy ; Drug Administration Schedule
Language	English
Publishing date	2022-12-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632784-9
ISSN	1099-0496 ; 8755-6863
ISSN (online)	1099-0496
ISSN	8755-6863
DOI	10.1002/ppul.26277
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Article: Effects of age and sex on the pharmacokinetics of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521).

Frey, Reiner / Saleh, Soundos / Becker, Corina / Mück, Wolfgang

Pulmonary circulation

2016 Volume 6, Issue Suppl 1, Page(s) S58–65

Abstract: Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). This randomized, double-blind, placebo-controlled study investigated the ... ...

Abstract	Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). This randomized, double-blind, placebo-controlled study investigated the pharmacokinetics of riociguat and its metabolite M1 in young (18-45 years) and elderly (64.5-80 years) healthy volunteers of both sexes to assist planning of the dose regimens for clinical trials. The data were also used to draw comparisons with the effects of age and sex on riociguat pharmacokinetics in patients with PAH and CTEPH from the riociguat phase 3 trials, PATENT and CHEST. Volunteers received an oral dose of either riociguat 2.5 mg or placebo, and the concentrations of riociguat and M1 in blood and urine samples were determined using mass spectrometry. In elderly healthy volunteers, overall riociguat and M1 exposure tended to be higher than in young healthy volunteers (P > 0.05), partly because of reduced renal clearance (approximately 28% reduction) and differences in body weight. Although the mean maximum concentrations of riociguat and M1 were significantly higher in women than in men (35% and 50% higher, respectively), total exposure was similar. Despite differences in riociguat and M1 pharmacokinetics, riociguat was well tolerated with a comparable safety profile across all subgroups, suggesting that differences in drug exposure due to age or sex were not sufficient to warrant a dose adjustment in clinical trials. Furthermore, similar pharmacokinetics were observed in patients with PAH and CTEPH. However, particular care should be exercised during individual dose titration of riociguat in elderly patients.
Language	English
Publishing date	2016-03-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2638089-4
ISSN	2045-8940 ; 2045-8932
ISSN (online)	2045-8940
ISSN	2045-8932
DOI	10.1086/685019
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Article: Population pharmacokinetics of single-dose riociguat in patients with renal or hepatic impairment.

Saleh, Soundos / Becker, Corina / Frey, Reiner / Mück, Wolfgang

Pulmonary circulation

2016 Volume 6, Issue Suppl 1, Page(s) S75–85

Abstract: This population pharmacokinetics (PK) analysis characterized the PK of the oral soluble guanylate cyclase stimulator riociguat in patients with renal or hepatic impairment and determined whether smoking affects riociguat dosing. Two phase 1 studies were ... ...

Abstract	This population pharmacokinetics (PK) analysis characterized the PK of the oral soluble guanylate cyclase stimulator riociguat in patients with renal or hepatic impairment and determined whether smoking affects riociguat dosing. Two phase 1 studies were performed in patients with renal impairment (n = 72, of whom 11 were smokers), and two were performed in those with hepatic impairment (n = 64, of whom 12 were smokers). Plasma and urine samples were collected after a single oral dose of riociguat 1.0 or 0.5 mg. Nonlinear mixed-effects modeling was used to develop a combined, two-compartment population PK model for riociguat and its main metabolite, M1. Riociguat and M1 clearance was split into renal and nonrenal parts; the nonrenal part for riociguat was divided into metabolism to M1 and a metabolic (nonrenal) part. Total clearance of riociguat was 1.912 L/h. The main route of riociguat clearance is metabolism to M1 (1.2 L/h). In this model, hepatic function biomarkers or Child-Pugh classification had no significant effect on riociguat or M1 clearance. Nonrenal (nonmetabolism) riociguat clearance was similar in all groups. Renal clearance (0.242 L/h) contributed less to riociguat total clearance, mainly determined by glomerular filtration (0.174 L/h). Renal impairment reduced riociguat and M1 clearance. Hepatic or renal impairment had limited effects on total exposure to riociguat. However, individual dose adjustment of riociguat should be administered with particular care in patients with moderate hepatic or renal impairment. Riociguat is not recommended in severe hepatic or renal impairment. Smoking reduced riociguat exposure by significantly increasing metabolism to M1.
Language	English
Publishing date	2016-03-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2638089-4
ISSN	2045-8940 ; 2045-8932
ISSN (online)	2045-8940
ISSN	2045-8932
DOI	10.1086/685647
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Article: Population pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of riociguat in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.

Saleh, Soundos / Becker, Corina / Frey, Reiner / Mück, Wolfgang

Pulmonary circulation

2016 Volume 6, Issue Suppl 1, Page(s) S86–96

Abstract: This analysis aimed to characterize the pharmacokinetics (PK) and PK/pharmacodynamic (PK/PD) relationship of riociguat and its metabolite M1 in patients with chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). ... ...

Abstract	This analysis aimed to characterize the pharmacokinetics (PK) and PK/pharmacodynamic (PK/PD) relationship of riociguat and its metabolite M1 in patients with chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). Blood samples were collected in two phase 3 studies-PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 12 weeks; PAH) and CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 16 weeks; CTEPH)-and long-term extensions. Patients were initially randomized to receive placebo or riociguat, and they received riociguat in the extensions. Nonlinear mixed-effects modeling was used to develop a population PK model describing riociguat PK. PK/PD relationships were investigated by comparing derived PK parameters with changes in PD parameters. Covariate analyses included smoking status, bosentan comedication, bilirubin levels, and baseline creatinine clearance. The PK of riociguat/M1 was described by a one-compartment model. Mean population estimates for riociguat absorption rate constant, clearance, and volume of distribution were 2.17/h, 1.81 L/h, and 32.3 L, respectively; for M1 they were 0.258/h, 3.16 L/h, and 124 L. Interindividual variability was moderate for riociguat and moderate to high for M1. There was no evidence of time- or dose-dependent changes in riociguat/M1 PK. Riociguat clearance was higher in smokers (120% increase) and bosentan-treated patients (36% increase) than in nonsmokers and those not receiving bosentan. There was an inverse correlation between bilirubin and riociguat clearance. In PK/PD analyses, 6-minute walk distance was related to hemodynamic parameters, particularly pulmonary vascular resistance. Riociguat PK were described by a one-compartment model. Effects of covariates on riociguat and M1 PK were established, and a PK/PD relationship was demonstrated. (ClinicalTrials.gov identifiers: PATENT-1, NCT00810693; PATENT-2, NCT00863681; CHEST-1, NCT00855465; CHEST-2, NCT00910429.).
Language	English
Publishing date	2016-03-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2638089-4
ISSN	2045-8940 ; 2045-8932
ISSN (online)	2045-8940
ISSN	2045-8932
DOI	10.1086/685404
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Article ; Online: Riociguat for the Treatment of Raynaud's Phenomenon: A Single-Dose, Double-Blind, Randomized, Placebo-Controlled Cross-Over Pilot Study (DIGIT).

Huntgeburth, Michael / Kießling, Johannes / Weimann, Gerrit / Wilberg, Verena / Saleh, Soundos / Hunzelmann, Nicolas / Rosenkranz, Stephan

Clinical drug investigation

2018 Volume 38, Issue 11, Page(s) 1061–1069

Abstract: Background and objective: Raynaud's phenomenon (RP) is characterized by transient digital ischemia and is commonly associated with connective tissue disease. Treatment remains unsatisfactory. Here we evaluate the efficacy, safety, and pharmacokinetics ... ...

Abstract	Background and objective: Raynaud's phenomenon (RP) is characterized by transient digital ischemia and is commonly associated with connective tissue disease. Treatment remains unsatisfactory. Here we evaluate the efficacy, safety, and pharmacokinetics of a single dose of the soluble guanylate cyclase stimulator riociguat in RP. Methods: DIGIT was a double-blind, randomized, placebo-controlled pilot study. Patients with primary or secondary RP were randomized to a single oral dose of riociguat 2 mg or placebo in a cross-over design (7 ± 3 days). Efficacy was assessed as placebo-corrected change in digital blood flow 2 h post-dose at room temperature (RT) or following cold exposure (CE), measured by laser-speckle contrast analysis. Patients were regarded as responders if placebo-corrected digital blood flow increased by ≥ 10% from baseline at RT or after CE. Results: Of 20 eligible patients, 17 (85%) were female and mean [standard deviation (SD)] age was 52 (13.8) years. Placebo-corrected changes in digital blood flow were + 46% [90% confidence interval (CI) - 6 to + 98] at RT and - 9% (90% CI - 63 to + 44) after CE, with high inter-individual variability. Eight patients (40%) were responders at RT, and 12 (60%) after CE. Riociguat increased mean (SD) digital blood flow in responders at RT by + 136% (114) and in responders following CE by + 39% (53). Riociguat was well tolerated, with few adverse events. Conclusion: In this pilot study, single-dose riociguat was well tolerated in patients with RP and resulted in improved digital blood flow in some patient subsets, with high inter-individual variability. Long-term evaluation is warranted.
MeSH term(s)	Administration, Oral ; Adult ; Aged ; Blood Flow Velocity/drug effects ; Blood Flow Velocity/physiology ; Cross-Over Studies ; Double-Blind Method ; Enzyme Activators/administration & dosage ; Female ; Fingers/blood supply ; Humans ; Male ; Middle Aged ; Pilot Projects ; Pyrazoles/administration & dosage ; Pyrimidines/administration & dosage ; Raynaud Disease/diagnosis ; Raynaud Disease/drug therapy ; Raynaud Disease/physiopathology ; Treatment Outcome
Chemical Substances	Enzyme Activators ; Pyrazoles ; Pyrimidines ; riociguat (RU3FE2Y4XI)
Language	English
Publishing date	2018-09-20
Publishing country	New Zealand
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	1220136-4
ISSN	1179-1918 ; 0114-2402 ; 1173-2563
ISSN (online)	1179-1918
ISSN	0114-2402 ; 1173-2563
DOI	10.1007/s40261-018-0698-1
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Article: Pharmacokinetic interaction of riociguat and antiretroviral combination regimens in HIV-1-infected adults.

DeJesus, Edwin / Saleh, Soundos / Cheng, Sue / van der Mey, Dorina / Becker, Corina / Frey, Reiner / Unger, Sigrun / Mueck, Wolfgang

Pulmonary circulation

2019 Volume 9, Issue 2, Page(s) 2045894019848644

Abstract: Riociguat, a first-in-class soluble guanylate cyclase stimulator, is approved for the treatment of pulmonary arterial hypertension (PAH), a serious potential complication of human immunodeficiency virus (HIV) infection. This open-label study investigated ...

Abstract	Riociguat, a first-in-class soluble guanylate cyclase stimulator, is approved for the treatment of pulmonary arterial hypertension (PAH), a serious potential complication of human immunodeficiency virus (HIV) infection. This open-label study investigated the pharmacokinetic drug-drug interaction potential of antiretroviral therapies on riociguat exposure in HIV-infected adults. HIV-infected adults without PAH on stable antiretroviral regimens (efavirenz/emtricitabine/tenofovir disoproxil, emtricitabine/rilpivirine/tenofovir disoproxil, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil, abacavir/dolutegravir/lamivudine, or a ritonavir-boosted triple regimen) for ≥ 6 weeks received a single riociguat dose (0.5 mg). Riociguat pharmacokinetics and safety were assessed; pharmacokinetics was compared with historical healthy volunteer data. Of 41 participants treated (n = 8 in each arm, except n = 9 in the ritonavir-boosted triple regimen arm), 40 were included in the pharmacokinetic analyses. Riociguat median t
Language	English
Publishing date	2019-03-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2638089-4
ISSN	2045-8940 ; 2045-8932
ISSN (online)	2045-8940
ISSN	2045-8932
DOI	10.1177/2045894019848644
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Article ; Online: Clinical Pharmacokinetic and Pharmacodynamic Profile of Riociguat.

Frey, Reiner / Becker, Corina / Saleh, Soundos / Unger, Sigrun / van der Mey, Dorina / Mück, Wolfgang

Clinical pharmacokinetics

2017 Volume 57, Issue 6, Page(s) 647–661

Abstract: Oral riociguat is a soluble guanylate cyclase (sGC) stimulator that targets the nitric oxide (NO)-sGC-cyclic guanosine monophosphate pathway with a dual mode of action: directly by stimulating sGC, and indirectly by increasing the sensitivity of sGC to ... ...

Abstract	Oral riociguat is a soluble guanylate cyclase (sGC) stimulator that targets the nitric oxide (NO)-sGC-cyclic guanosine monophosphate pathway with a dual mode of action: directly by stimulating sGC, and indirectly by increasing the sensitivity of sGC to NO. It is rapidly absorbed, displays almost complete bioavailability (94.3%), and can be taken with or without food and as crushed or whole tablets. Riociguat exposure shows pronounced interindividual (60%) and low intraindividual (30%) variability in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), and is therefore administered using an individual dose-adjustment scheme at treatment initiation. The half-life of riociguat is approximately 12 h in patients and approximately 7 h in healthy individuals. Riociguat and its metabolites are excreted via both renal (33-45%) and biliary routes (48-59%), and dose adjustment should be performed with particular care in patients with moderate hepatic impairment or mild to severe renal impairment (no data exist for patients with severe hepatic impairment). The pharmacodynamic effects of riociguat reflect the action of a vasodilatory agent, and the hemodynamic response to riociguat correlated with riociguat exposure in patients with PAH or CTEPH in phase III population pharmacokinetic/pharmacodynamic analyses. Riociguat has a low risk of clinically relevant drug interactions due to its clearance by multiple cytochrome P450 (CYP) enzymes and its lack of effect on major CYP isoforms and transporter proteins at therapeutic levels. Riociguat has been approved for the treatment of PAH and CTEPH that is inoperable or persistent/recurrent after surgical treatment.
MeSH term(s)	Administration, Oral ; Animals ; Drug Interactions ; Humans ; Hypertension, Pulmonary/metabolism ; Pyrazoles/blood ; Pyrazoles/pharmacokinetics ; Pyrazoles/pharmacology ; Pyrimidines/blood ; Pyrimidines/pharmacokinetics ; Pyrimidines/pharmacology ; Soluble Guanylyl Cyclase
Chemical Substances	Pyrazoles ; Pyrimidines ; Soluble Guanylyl Cyclase (EC 4.6.1.2) ; riociguat (RU3FE2Y4XI)
Language	English
Publishing date	2017-10-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-017-0604-7
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Article: Riociguat in children with pulmonary arterial hypertension: The PATENT-CHILD study.

García Aguilar, Humberto / Gorenflo, Matthias / Ivy, D Dunbar / Moledina, Shahin / Castaldi, Biagio / Ishida, Hidekazu / Cześniewicz, Paweł / Kusa, Jacek / Miera, Oliver / Pattathu, Joseph / Weng, Ken-Pen / Ablonczy, Laszlo / Apitz, Christian / Katona, Marta / Kurosaki, Kenichi / Pulido, Tomas / Yamagishi, Hiroyuki / Yasuda, Kazushi / Cisternas, Galia /

Goth, Melanie / Lippert, Susanne / Radomskyj, Anna / Saleh, Soundos / Willmann, Stefan / Wirsching, Gabriela / Bonnet, Damien / Beghetti, Maurice

Pulmonary circulation

2022 Volume 12, Issue 3, Page(s) e12133

Abstract: Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in ... ...

Abstract	Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT-CHILD (NCT02562235), a multicenter, single-arm, 24-week, open-label, Phase 3 study. Patients aged 6-17 years in World Health Organization functional class (WHO-FC) I-III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5-2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty-four patients (mean age 12.8 years), 18 of whom were in WHO-FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study-drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6-minute walking distance was 23 ± 69 m (
Language	English
Publishing date	2022-07-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2638089-4
ISSN	2045-8940 ; 2045-8932
ISSN (online)	2045-8940
ISSN	2045-8932
DOI	10.1002/pul2.12133
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Article: Bioavailability, pharmacokinetics, and safety of riociguat given as an oral suspension or crushed tablet with and without food.

Saleh, Soundos / Frey, Reiner / Becker, Corina / Unger, Sigrun / Wensing, Georg / Mück, Wolfgang

Pulmonary circulation

2015 Volume 6, Issue Suppl 1, Page(s) S66–74

Abstract: Riociguat is approved for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Some patients have difficulty swallowing tablets; therefore, 2 randomized, nonblinded, crossover studies compared the relative ... ...

Abstract	Riociguat is approved for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Some patients have difficulty swallowing tablets; therefore, 2 randomized, nonblinded, crossover studies compared the relative bioavailability of riociguat oral suspensions and immediate-release (IR) tablet and of crushed-tablet preparations versus whole IR tablet. In study 1, 30 healthy subjects received 5 single riociguat doses: 0.3 and 2.4 mg (0.15 mg/mL suspensions), 0.15 mg (0.03 mg/mL), and 1.0 mg (whole IR tablet) under fasted conditions and 2.4 mg (0.15 mg/mL) after a high-fat, high-calorie American-style breakfast. In study 2, 25 healthy men received 4 single 2.5-mg doses: whole IR tablet and crushed IR tablet suspended in applesauce and water, respectively, under fasted conditions, and whole IR tablet after a continental breakfast. In study 1, dose-normalized pharmacokinetics of riociguat oral suspensions and 1.0-mg whole IR tablet were similar in fasted conditions; 90% confidence intervals for riociguat area under the curve (AUC) to dose and mean maximum concentration (C max) to dose were within bioequivalence criteria. After food, dose-normalized AUC and C max decreased by 15% and 38%, respectively. In study 2, riociguat exposure was similar for all preparations; AUC ratios for crushed-IR-tablet preparations to whole IR tablet were within bioequivalence criteria. The C max increased by 17% for crushed IR tablet in water versus whole IR tablet. Food intake decreased C max of the whole tablet by 16%, with unaltered AUC versus fasted conditions. Riociguat bioavailability was similar between the oral suspensions and the whole IR tablet; exposure was similar between whole IR tablet and crushed-IR-tablet preparations. Minor food effects were observed. Results suggest that riociguat formulations are interchangeable.
Language	English
Publishing date	2015-11-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2638089-4
ISSN	2045-8940 ; 2045-8932
ISSN (online)	2045-8940
ISSN	2045-8932
DOI	10.1086/685020
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