Pharmacology Update
Riociguat Tablets
(Adempas®)
By William T. Elliott, MD, FACP, and
James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern
California Kaiser Permanente; and Assistant Professor
of Medicine, University of California, San Francisco.
Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field
of study.
The first in the class of soluble guanylate cyclase (sGC) stimulators has been approved by the FDA for the treatment of pulmonary hypertension. Riociguat was given a priority review, which provides for expedited review of drugs that may offer major advances in treatment. It is marketed by Bayer HealthCare Pharmaceuticals as Adempas.
Indications
Riociguat is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment or inoperable CTEPH, and pulmonary arterial hypertension (PAH) secondary to connective tissue disease or of unknown cause.1 The desired clinical response is improved exercise capacity and WHO functional class, and delay in clinical worsening (especially for PAH).
Dosage
The recommended starting dose is 1 mg three times a day.1 For patients who are intolerant of the hypotensive effect, the starting dose should be reduced to 0.5 mg three times daily. The dose may be increased at 0.5 mg increments at no less than 2 week intervals to a maximum dose of 2.5 mg three times daily. The starting dose should be 0.5 mg three times a day if coadministered with a strong CYP or P-gp/BCRP inhibitor. Strong CYP inducers may reduce the systemic exposure of riociguat. Coadministration with an antacid should be separated by at least 1 hour.
Riociguat is available as 0.5 mg, 1 mg, 2 mg, and 2.5 mg tablets.
Potential Advantages
Riociguat is the first drug to be effective in CTEPH. It also provides an agent with a different mechanism of action to treat PAH.
Potential Disadvantages
Common adverse events associated with riociguat are headache (27% vs 18% placebo), dyspepsia/gastritis (21% vs 8%), dizziness (20% vs 13%), diarrhea (12% vs 8%), hypotension (10% vs 4%), and anemia (7% vs 2%).
Comments
Riociguat has a dual action on the nitric acid-sGC-cCMP pathway. It stabilizes nitric acid-sGC binding as well as directly stimulating sGC.1 This leads to increased production of cCMP and vasodilation. In contrast, phosphodiesterase inhibitors such as sildenafil slow the degradation of cCMP. The efficacy and safety of riociguat were evaluated in two, double-blind, placebo-controlled, parallel studies, one for PAH and one for CTEPH. In the first study (PATIENT-1), 405 subjects with mainly idiopathic PAH (60%) and connective tissue disease (25%) and Functional Class II-III at baseline were randomized 4:1:2 to riociguat titrated between 1 and 2.5 mg, titrated between 1 and 1.5 mg, and placebo. The primary endpoint was the change from baseline in distance walked in 6 minutes (6MWD) at week 12. The overall mean baseline 6MWD was 363 meters. Approximately 75% were titrated to the maximum dose of 2.5 mg three times daily. The mean drug effect was about 30 meters compared to -6 meters for placebo (least square difference of 36 m (95% CI, 20-52; P < 0.001). Seventy-six percent of patients on riociguat showed an improvement in 6MWD of 20 meters compared to 59% on placebo. Twenty-one percent had improvement in WHO Functional Class compared to 14% for placebo. Four percent had deterioration on riociguat compared to 14% for placebo. Benefit was seen by week 2 and there was no difference in drug effect between those with WHO III/IV treatment-naïve or those previously treated with an endothelin receptor antagonist or prostacyclin. In the second study (CHEST-1), 262 subjects with CTEPH were randomized 2:1 to riociguat titrated 1 to 2.5 mg or placebo. The primary endpoint was 6MWD. Secondary endpoints included change in pulmonary vascular resistance and WHO functional class. At week 16, the riociguat group showed a mean increase of 39 meters compared to -6 meters for placebo. The least square mean difference was 46 meters (95% CI, 25-67; P < 0.001). Riociguat also showed significant improvement in pulmonary vascular resistance and WHO functional class. In the open-label extensions of both PATIENT-1 (n = 363) and CHEST-1 (n = 237), with mean treatment durations of 663 (± 319) and 582 (± 317) days, the probability of survival at year 2 was 93% and 94%, respectively.1
Clinical Implications
Limited treatment options exist for patients with pulmonary hypertension, especially for those with CTEPH for whom pulmonary thromboendarterectomy has been the only option. Riociguat is approved for both CTEPH and for idiopathic PAH, or PAH caused by connective tissue disease. CTEPH and PAH are both serious, life-threatening conditions with a survival of several months to several years, depending on severity. For CTEPH, riociguat is an option in patients with symptoms after surgery or for those who are are inoperable. For PAH, there are currently several pharmacotherapeutic options, including prostanoids, endothelin-receptor antagonists, and phosphodiesterase inhibitors. Riociguat offers an orally effective drug with a different mechanism of action. The benefit of riociguat is, however, modest. The magnitude of the improvement in 6MWD is similar to that reported for bosentan and sildenafil.4,5 The monthly wholesale acquisition cost for riociguat (2.5 mg three times daily) is $7500 compared to $6840 for bosentan (125 mg twice daily), $1920 (branded sildenafil 20 mg three times daily), and $364 (generic sildenafil).
References
- Adempas Prescribing Information. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc.; October 2013.
- Ghofrani NA, et al. N Engl J Med 2013;369:330-340.
- Ghofrani NA, et al. N Engl J Med 2013;369:319-329.
- Rubin LJ, et al. N Engl J Med 2002;346:896-903.
- Galie N, et al. N Engl J Med 2005;353:2148-2157.
