Riociguat

Riociguat is a Vasodilator / Soluble Guanylate Cyclase Stimulator that acts as an antihypertensive agent to treat pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension.

Riociguat is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability of Approx 94%.The volume of distribution was found to be Approx 30 L with Plasma protein binding of Approx 95% mainly to serum albumin and α1-acid glycoprotein. It gets metabolized by CYP1A1, 3A4, 2C8, and 2J2 enzymes to an active metabolite, M1, then further metabolized to an inactive metabolite, N-glucuronide. It gets excreted via feces (approx 53%); urine (approx 40%) with an elimination half-life of approx 7 hours.

The common side effects are Dyspepsia, nausea, diarrhea, vomiting, gastroenteritis, gastritis, GERD, dysphagia, abdominal pain, constipation, abdominal distention, etc.

Riociguat is available in the form of a dosage form such as tablets.

Riociguat is available in Switzerland, Europe, India, Japan, the U.S

Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes the synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP).

The Duration of Action of Riociguat was within 5–10 hours.

The Tmax was about 1.5 hours and Cmax was about 1-1.5 h, respectively

Riociguat is available in the form of tablets.

For Tablets:

Riociguat tablets should be taken orally by mouth with or without water.

Riociguat, a soluble guanylate cyclase (sGC) stimulator, exhibits a vasodilatory and NO‐like effect by direct stimulation of the sGC enzyme, thus circumventing the need for NO stimulation and compensating for decreased NO sensitivity in vascular pathology.

Riociguat is a Vasodilator / Soluble Guanylate Cyclase Stimulator which acts as an antihypertensive agent used in the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension.

Riociguat is approved for use in the following clinical indications

Pulmonary Arterial Hypertension (PAH)

Riociguat is indicated for the treatment of adults with pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity, WHO functional class, and to delay clinical worsening. Efficacy was shown in patients on Riociguat monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%)

Chronic thromboembolic pulmonary hypertension.

Riociguat is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Riociguat is available in various dosage strengths of 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg.

Riociguat is available in the form of tablets.

Riociguat should be used for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per the patient's requirements.

Riociguat may be contraindicated in the following

• Pulmonary hypertension is associated with idiopathic interstitial pneumonias (PH-IIP).
• Severe hepatic impairment (Child-Pugh C).
• Pregnancy and lactation.
• Concomitant use with nitrates or nitric acid donors, phosphodiesterase (PDE-5) inhibitors (e.g. sildenafil, tadalafil, vardenafil).

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Embryo-Fetal Toxicity

Based on data from animal reproduction studies, Riociguat may cause embryo-fetal toxicity when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test before the start of treatment, monthly during treatment, and for one month after stopping treatment. Advise females of reproductive potential to use effective contraception during treatment with RIOCIGUAT and for at least one month after the last dose.

For females, Riociguat is only available through a restricted program under the Riociguat REMS Program

Hypotension

Riociguat decreases blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-GP/BCRP inhibitors

Hematoma, hematemesis, and intra-abdominal hemorrhage.

Pulmonary Veno-Occlusive Disease

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with the pulmonary venous-occlusive disease (PVOD). Therefore, the administration of Riociguat to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and, if confirmed, discontinue treatment with Riociguat.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Carcinogenicity studies of riociguat were conducted in mice and rats. In mice, oral administration of riociguat (up to 25 mg/kg/day in males and 32 mg/kg/day in females) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 6 times the human’s exposure.

In rats, oral administration of riociguat (up to 20 mg/kg/day) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 7 times the human exposure.

Mutagenesis

Riociguat and M1 did not show genotoxic potential in the in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in Chinese hamster V79 cells, or the in vivo micronucleus assay in the mouse.

Impairment Of Fertility

In rats, no effects on male or female fertility were observed.

In male rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and throughout the mating period had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure based on body surface area. In female rats, oral administration of riociguat (up to 30 mg/kg/day) before and during mating and continuing to gestation on Day 7 did not affect fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area.

Alcohol consumption with RIOCIGUAT may increase the risk of low blood pressure and cause adverse effects, such as Dizziness, fainting, light-headedness, or headache.

Riociguat use in breastfeeding patients is not recommended.

Pregnancy Category X

Risk Summary

Riociguat may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy.

Riociguat was teratogenic and embryotoxic in rats at doses with exposures to an unbound drug that was approximately 8 Times and 2 times, respectively, the human exposure. In rabbits, riociguat led to abortions at 4 times the human exposure and fetal toxicity with exposures approximately 13 times the human exposure. If Riociguat is used in pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

Avoid smoking tobacco while taking riociguat. Riociguat doses higher than 2.5 mg three times a day may be considered to match exposure seen in nonsmoking patients. In patients who smoke tobacco, plasma concentrations of riociguat are reduced by 50% to 60% compared to nonsmokers.

Decreased serum concentration with St. John’s wort.

The adverse reactions related to the molecule Riociguat can be categorized as

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripheral ischemia, dry mouth, asthenia, and somnolence.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Riociguat are briefly summarized here.

• Decreased serum concentration with antacids, PPI, and CYP3A4 inducers (e.g., phenytoin, rifampicin).
• Increased plasma concentration with CYP1A1 (e.g. erlotinib), CYP3A4 inhibitors (e.g., clarithromycin), potent P-GP/BCRP inhibitors (e.g. ciclosporin, azole antifungals, protease inhibitors).
• Potentially Fatal: Enhanced hypotensive effect with amyl nitrate, nitroglycerin, and PDE-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms:

Pronounced hypotension.

Management:

Supportive treatment.

Pharmacodynamics:

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes the synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis, and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide, and insufficient stimulation of the NO-sGC-cGMP pathway.

Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.

Pharmacokinetics:

• Absorption:

The pharmacokinetics of riociguant are dose-proportional from 0.5 mg to 2.5 mg. The absolute bioavailability is approximately 94%. After oral administration, peak plasma concentrations were achieved within 1.5 hours. Food does not affect the bioavailability of riociguat.

• Distribution:

The volume of distribution: Approx 30 L. Plasma protein binding: Approx 95% mainly to serum albumin and α1-acid glycoprotein.

• Metabolism:

Metabolized by CYP1A1, 3A4, 2C8, and 2J2 enzymes to an active metabolite, M1, then further metabolized to an inactive metabolite, N-glucuronide.

• Excretion:

It gets excreted Via faeces (approx 53%); urine (approx 40%). Elimination half-life: Approx 7 hours

1. https://www.rxlist.com/Riociguat-drug.htm#precautions
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218670/
3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204819s006lbl.pdf
4. Ghofrani HA, Galiè N, et.al., Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369:330-40.
5. Ghofrani HA, Voswinckel R, et.,al. F. Riociguat for pulmonary hypertension. Future Cardiology. 2010 Mar;6(2):155-66.
6. https://www.mims.com/malaysia/drug/info/riociguat?mtype=generic
7. https://go.drugbank.com/drugs/DB08931