Riociguat

Overview

Riociguat, sold under the brand name Adempas, is a medication by Bayer that is a stimulator of soluble guanylyl cyclase (sGC). It is used to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of the class of sGC stimulators. The drug has a half-life of 12 hours and will decrease dyspnea associated with pulmonary arterial hypertension.[1] WP

It is available as a generic medication.[2] WP

Risks and side effects

Contraindications

Riociguat can cause fetal harm and is therefore contraindicated in pregnant women.[3] WP

The substance is also contraindicated in pulmonary hypertension in combination with idiopathic interstitial pneumonia (PH-IIP). A clinical trial testing riociguat for this purpose was prematurely terminated because it increased severe adverse effects and mortality in patients with pulmonary hypertension caused by idiopathic interstitial pneumonia when compared to placebo.[4] WP

Adverse effects

Serious adverse effects in clinical trials included bleeding. Hypotension (low blood pressure), headache, and gastrointestinal disorders also occurred.[3] WP

Interactions

Interactions

Nitrates and phosphodiesterase inhibitors (including PDE5 inhibitors) increase the hypotensive (blood pressure lowering) effect of riociguat. Combining such drugs is therefore contraindicated. Riociguat levels in the blood are reduced by tobacco smoking and strong inducers of the liver enzyme CYP3A4, and increased by strong cytochrome inhibitors.[3] WP

Interaction study with sildenafil

This study investigated safety, tolerability, pharmacokinetics and the impact on pulmonary and systemic haemodynamics of single doses of 0.5 and 1 mg of riociguat in patients with PAH and stable treatment of sildenafil (20 mg thrice daily) in a non-randomized uncontrolled trial. The study showed potentially unfavorable safety signals with sildenafil plus riociguat and no evidence of a positive benefit/risk ratio. Therefore, the concomitant use of riociguat with phosphodiesterase-5 inhibitors is contraindicated.[5] WP

Pharmacology

Pharmacology

Riociguat at concentration between 0.1 and 100 μM stimulates in a dose-dependent manner sGC activity up to 73-fold. In addition, it acts synergistically with diethylamine/NO, the donor of NO, to increase sGC activity in vitro up to 112-fold. A phase I study showed that riociguat is rapidly absorbed, and maximum plasma concentration is reached between 0.5 and 1.5 h. The mean elimination half-life appears to be 5–10 hours. Riociguat plasma concentrations have been also shown to be quite variable between patients, indicating that for clinical use it is probably necessary to titrate the drug specifically for each individual.[6][7] WP

History

Discovery

The first nitric oxide (NO) independent, haem-dependent sGC stimulator, YC-1, a synthetic benzylindazole derivative, was described in 1978. The characterisation 20 years later demonstrated that as well as increasing sGC activity, YC-1 acted in synergy with NO to stimulate sGC. However, YC-1 was a relatively weak vasodilator and had side effects. Therefore, the search began for novel indazole compounds that were more potent and more specific sGC stimulators. The result was the identification of BAY 41-2272 and BAY 41–8543. Both compounds were tested in various preclinical studies on different animal models and appeared to improve systemic arterial oxygenation. To improve the pharmacologic and pharmacokinetic profile an additional 1000 compounds were screened leading to the discovery of riociguat. Riociguat was tested in mouse and rat disease models, where it effectively reduced pulmonary hypertension and reversed the associated right heart hypertrophy and ventricular remodelling.[8–11] WP⚠ Wikipedia itself has flagged this text: vague.

Several clinical trials have been undertaken to investigate and evaluate diverse aspects of riociguat, and some of them are still ongoing.[12] WP

Phase i clinical trials

One of the first studies was designed to test the safety profile, pharmacokinetics and pharmacodynamics of single oral doses of riociguat (0.25–5 mg). 58 healthy male subjects were given riociguat orally (oral solution or immediate-release tablet) in a randomised, placebo-controlled trial. Doses of riociguat were increased stepwise, and riociguat was well tolerated up to 2.5 mg.[7] WP

Phase II clinical trials

A proof-of-concept study, reported by the University of Gießen Lung Center, was the first small study (in 4 PAH patients) to investigate safety, tolerability, pharmacokinetics and efficacy parameters. The drug was well tolerated and superior to NO in efficacy and duration.[13] WP

An open-label, non-controlled phase II trial of riociguat in 75 adult patients (42 with CTEPH and 33 with PAH, all in World Health Organization (WHO) functional class II or III) evaluated the safety and tolerability, and the effects on hemodynamics, exercise capacity and functional class. Riociguat was given three times daily for 12 weeks. Doses were titrated at 2-week intervals from 1.0 mg three times daily to a maximum of 2.5 mg three times daily. Riociguat had a favourable safety profile, and also significantly improved exercise capacity and hemodynamic parameters such as pulmonary vascular resistance, cardiac output and pulmonary arterial pressure compared to baseline values.[14] WP

In addition, a phase II study of riociguat is underway in patients with other forms of PH such as associated with interstitial lung disease (PH-ILD).[15] WP

Phase III clinical trials

The phase III trials on riociguat are multi-center studies. The study program included large randomized, double-blind, placebo-controlled pivotal trial phase (CHEST-1 and PATENT-1), and open-label extensions of these studies (CHEST-2 and PATENT-2). Details of these studies are reported on ClinicalTrials.gov, a register of studies maintained by the National Institutes of Health (NIH).[12] WP

CHEST

The Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial (CHEST) was a randomized, placebo-controlled trial aimed to analyse the efficacy and safety of riociguat in CTEPH patients. After a 16-week riociguat treatment the patient's exercise capacity were evaluated by measuring the change in the six-minute walk test (6-MWT). Patients having completed CHEST-1 were invited to enter the extension trial, CHEST-2. The first interim analysis of CHEST-2 showed that riociguat was well tolerated, with a good long-term safety profile in patients with CTEPH.[16][17][18] WP

PATENT

The Pulmonary Arterial Hypertension sGC-Stimulator Trial (PATENT) was a randomized, placebo-controlled trial that investigated the efficacy and safety of riociguat in PAH patients. After a 12-week treatment the patient's exercise capacity was evaluated by measuring the change in the 6-MWT. Patients having completed PATENT-1 were invited to enter the extension trial, PATENT-2. The first interim analysis of PATENT-2 showed that at one year, long-term riociguat was well tolerated in patients with PAH and showed sustained benefits in 6MWD and WHO FC. The safety profile of riociguat in PATENT-2 was similar to that observed in PATENT-1.[19][20] WP

Effect of riociguat on bone metabolism

This randomized, double blind, placebo controlled Phase I study investigated the effect of riociguat, administered as 2.5 mg immediate-release (IR)-tablets twice daily over 14 days, on the bone metabolism. Effects on bone formation had been seen in growing, juvenile and adolescent rats. In juvenile rats, the changes consisted of thickening of trabecular bone and hyperostosis and remodeling of metaphyseal and diaphyseal bone, whereas in adolescent rats an overall increase of bone mass was observed. On the other hand, no such effects were observed in adult rats.[21] WP

Chemistry

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

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Sources

1. Other Background Riociguat
2. Journal / agency 2022 First Generic Drug Approvals. 3 March 2023
3. Other Riociguat Drugs.com pro adempas-tablets
4. Journal / agency Adempas not for use in patients with pulmonary hypertension caused by idiopathic interstitial pneumonia. 24 June 2016
5. Other ClinicalTrialsGov NCT00680654 Interaction Study in Patients With Pulmonary Hypertension and Stable Treatment of Sildenafil 20 mg TID
6. Journal / agency Schermuly RT, Stasch JP, Pullamsetti SS, Middendorff R, Müller 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. The European Respiratory Journal. October 2008. doi:10.1183/09031936.00114407 · PMID 18550612
7. Journal / agency Frey R, Mück W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G. Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers. Journal of Clinical Pharmacology. December 2008. doi:10.1177/0091270008322906 · PMID 18779378
8. Journal / agency Yoshina S, Tanaka A, Kuo SC. Studies on heterocyclic compounds. XXXVI. Synthesis of furo[3,2-cpyrazole derivatives. (4) Synthesis of 1,3-diphenylfuro[3,2-c]pyrazole-5-carboxaldehyde and its derivatives (author's transl)]. Yakugaku Zasshi. March 1978. doi:10.1248/yakushi1947.98.3_272 · PMID 650406
9. Journal / agency Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Gerzer R, Minuth T, Perzborn E, Pleiss U, Schröder H, Schroeder W, Stahl E, Steinke W, Straub A, Schramm M. NO-independent regulatory site on soluble guanylate cyclase. Nature. March 2001. doi:10.1038/35065611 · PMID 11242081
10. Journal / agency Evgenov OV, Pacher P, Schmidt PM, Haskó G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nature Reviews. Drug Discovery. September 2006. doi:10.1038/nrd2038 · PMID 16955067 · PMC2225477
11. Journal / agency Mittendorf J, Weigand S, Alonso-Alija C, Bischoff E, Feurer A, Gerisch M, Kern A, Knorr A, Lang D, Muenter K, Radtke M, Schirok H, Schlemmer KH, Stahl E, Straub A, Wunder F, Stasch JP. Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem. May 2009. doi:10.1002/cmdc.200900014 · PMID 19263460 · PMC3313366
12. Other ClinicalTrials.gov: Riociguat
13. Journal / agency Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bölkow D, Weissmann N, Mück W, Unger S, Wensing G, Schermuly RT, Ghofrani HA. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. The European Respiratory Journal. April 2009. doi:10.1183/09031936.00039808 · PMID 19129292
14. Other ATS International conference. 2009
15. Other ClinicalTrialsGov NCT00694850 Impact of Multiple Doses of BAY 63-2521 on Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Patients With Interstitial Lung Disease (ILD) Associated Pulmonary Hypertension
16. Journal / agency Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. The New England Journal of Medicine. July 2013. doi:10.1056/NEJMoa1209657 · PMID 23883377
17. Other ClinicalTrialsGov NCT00855465 A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH
18. Other ClinicalTrialsGov NCT00910429 BAY63-2521 - Long-term Extension Study in Patients With Chronic Thromboembolic Pulmonary Hypertension
19. Other ClinicalTrialsGov NCT00810693 A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With Pulmonary Arterial Hypertension (PAH)
20. Other ClinicalTrialsGov NCT00863681 BAY63-2521:Long-term Extension Study in Patients With Pulmonary Arterial Hypertension
21. Other ClinicalTrialsGov NCT00855660 Effect of Riociguat on Bone Metabolism

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