Riociguat
Riociguat, sold under the brand name Adempas, is a medication by Bayer that is a stimulator of soluble guanylyl cyclase. It is used to treat two forms of pulmonary hypertension : chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension. 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.
It is available as a generic medication.
Contraindications
Riociguat can cause fetal harm and is therefore contraindicated in pregnant women.The substance is also contraindicated in pulmonary hypertension in combination with idiopathic interstitial pneumonia. 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.
Adverse effects
Serious adverse effects in clinical trials included bleeding. Hypotension, headache, and gastrointestinal disorders also occurred.Interactions
s and phosphodiesterase inhibitors increase the hypotensive 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.Chemistry and mechanism of action
In healthy individuals, nitric oxide acts as a signaling molecule on vascular smooth muscle cells to induce vasodilation. NO binds to soluble guanylate cyclase and mediates the synthesis of the secondary messenger cyclic guanosine monophosphate. sGC forms heterodimers consisting of a larger alpha-subunit and a smaller haem-binding beta-subunit. The synthesised cGMP acts as a secondary messenger and activates cGMP-dependent protein kinase to regulate cytosolic calcium ion concentration. This changes the actin–myosin contractility, which results in vasodilation. NO is produced by the enzyme endothelial nitric oxide synthetase. In patients with pulmonary arterial hypertension eNOS levels are reduced. This results in overall lower levels of endothelial cell-derived NO and reduced vasodilation of smooth muscle cells. NO also reduces pulmonary smooth muscle cell growth and antagonises platelet inhibition, factors which play a key role in the pathogenesis of PAH.In contrast to NO- and haem-independent sGC activators like cinaciguat, the sGC stimulator riociguat directly stimulates sGC activity independent of NO and also acts in synergy with NO to produce anti-aggregatory, anti-proliferative, and vasodilatory effects.
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.History
Discovery
The first nitric oxide 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.Several clinical trials have been undertaken to investigate and evaluate diverse aspects of riociguat, and some of them are still ongoing.
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. 58 healthy male subjects were given riociguat orally in a randomised, placebo-controlled trial. Doses of riociguat were increased stepwise, and riociguat was well tolerated up to 2.5 mg.Phase II clinical trials
A proof-of-concept study, reported by the University of Gießen Lung Center, was the first small study to investigate safety, tolerability, pharmacokinetics and efficacy parameters. The drug was well tolerated and superior to NO in efficacy and duration.An open-label, non-controlled phase II trial of riociguat in 75 adult patients 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.
In addition, a phase II study of riociguat is underway in patients with other forms of PH such as associated with interstitial lung disease.