By: Hayeon Na, Co-Copy Editor [Content-Focused]

–

On October 8^th of 2013, Bayer’s new drug riociguat (Adempas®) was approved for the treatment of patients whose pulmonary hypertension (PH) belongs in WHO groups 1 and 4.¹ Riociguat (Adempas^®) is a soluble guanylate cyclase (sGC) stimulator, and currently the only one of its kind on the market.

Pulmonary hypertension is high blood pressure in the pulmonary arteries, veins, or capillaries which transport blood to and from the lungs. PH is a syndrome of restricted blood flow to these vessels, and can lead to shortness of breath during routine activities, and may limit all physical activity as it worsens.² In poorly managed PH, the resulting increase in vascular resistance leads to right heart failure. Due to the high pressure, the blood cannot be transported easily, and the right ventricle that pump the blood to these arteries becomes fatigued and weak.³ This eventually results in right heart failure, the major cause of death in patients with PH.³

In patients with PH, the average blood pressure is higher than 25mmHg in the pulmonary arteries, whereas the normal pressure is 8-20mmHg at rest.² Multiple etiologies have been identified including genetics, coronary artery disease, chronic obstructive pulmonary disease (COPD), and thrombosis.³ Pathogenic pathways that have been implicated in PH involves the genetic and molecular processes of the smooth muscle cells, endothelial cells (cells lining the interior of vessels), and adventitia (the outer most layer of connective tissue).³

PH is categorized into six groups based on its specific characteristics, such as its pathology, patho-biology, genetics, epidemiology, and risk factors.⁴ According to the European Society of Cardiology and the European Respiratory Society (ESC/ERS), the six groups are as seen in Table 1.⁴

These groups specify what “kind” of PH the patient has, which helps determine the treatment course.

On the other hand, PH is also divided into four functional classes through the New York Heart Association (NYHA) scale (1-4, with 4 being the worst) and the World Health Organization (WHO) scale (I-IV, with IV being the worst).³ The classes stratify the functional class, a measure of the limits that the

Table 1: Classification of Pulmonary Hypertension⁴

disease poses onto the patients. In practice, the NYHA scale and the WHO functional class scale are used interchangeably to categorize patients into functional classes.One aspect to note is that although the two scales are almost identical, the WHO functional classes factors in syncope or near-syncope into consideration due to its importance in the prognosis of patients with PH .⁵ The following table that describes the functional assessment categories is reprinted from the American College of Chest Physicians (ACCP) guidelines on pulmonary arterial hypertension (PAH ).⁶

The current treatment is based on rectifying the imbalance between the constrictive and dilatory effects on the pulmonary vessels; however, the American College of Cardiology Foundation and American Heart Association (ACCF/AHA) 2009 Guidelines notes that the imbalance in the remodeling of the vessels with excessive proliferation has been recognized as an important factor in disease progression and treatment.³ The current therapy includes the use of anticoagulants, diuretics, oxygen therapy, and digoxin as background therapies for management of signs and symptoms in patients without contraindications. Candidates for long-term calcium channel blocker (CCB) therapy may receive these drugs for dilation of the vessels. Those who cannot use CCBs, or are unresponsive, receive oral endothelin receptor antagonists (ERAs) or Phosphodiesterase-5 (PDE-5) inhibitors, and/or inhaled or injected prostanoids.³

Riociguat (Adempas®) is approved for two indications: Persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension (CTEPH, or WHO Group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class, and Pulmonary Arterial Hypertension (PAH or WHO Group 1) to improve exercise capacity, improve WHO functional class, and to delay clinical worsening.^7,8 It is a stimulator of the cardiopulmonary enzyme soluble guanylate cyclase (sGC), which is also a receptor of nitric oxide. Nitric oxide (NO) is a vasodilator that relaxes the smooth muscles of the blood vessels and helps balance blood pressure. Upon binding, the NO-sGC catalyzes the synthesis of cyclic guanosine monophosphate (cGMP), a signaling molecule that is a major factor in the regulation of vascular tone, proliferation, fibrosis and inflammation. By stimulating the sGC, riociguat (Adempas^®) targets the factors associated with pulmonary hypertension, such as endothelial dysfunction, impaired synthesis of nitric oxide and inadequate stimulation of the NO-sGC-cGMP pathway. Riociguat (Adempas^®) works in two ways: it stabilizes the bond between NO and sGC and thus sensitizes sGC to endogenous NO, and it also directly binds sGC at a different binding site than NO. The resulting increase in cGMP leads to vasodilation.⁷

Riociguat (Adempas®) comes in tablets of different strength ranging from 0.5 mg to 2.5 mg. The therapy is typically initiated at 1 mg by mouth three times daily. This may be increased by 0.5 mg at a time, though not more often than every two weeks, until a satisfactory therapeutic effect is achieved and if it is tolerated at a systolic blood pressure of 95mmHg or higher. The effects of the drug at doses higher than 2.5 mg three times daily have not been established, and should be closely monitored by the prescriber.⁷ If doses are missed for three days or more, re-titration is required.⁷ Patients should be monitored for blood pressure, significant peripheral edema, pulmonary function, bleeding, and exercise tolerance to assess the effectiveness and the safety of the medication.

The pharmacokinetics of riociguat (Adempas^®) is dose proportional from 0.5 mg to 2.5 mg. It has an oral bioavailability of 94%, reaches the peak plasma concentration within 1.5 hours, and has a volume of distribution at steady state of 30 L. It is highly protein bound (95%) and has an elimination half-life of about 12 hours.⁷

Riociguat (Adempas^®) has many sources for drug-drug interactions. It is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), both of which may function as drug efflux pumps in excretion of drugs.⁷ When taken with drugs that may induce or inhibit P-gp or BCRP, the plasma concentration of riociguat (Adempas^®) will most likely be altered. ⁷ The drug is mainly cleared by enzymes cytochrome P-450 monooxygenase (CYP) 1A1, 3A, 2C8 and 2J2. The major metabolite M1 is catalyzed by CYP1A1, which is inducible by polycyclic aromatic hydrocarbons such as those present in cigarette smoke or charred food.⁷ The product’s package insert notes that in regular smokers (the frequency and amount of cigarettes was unspecified), the plasma concentration of the drug is reduced to almost 50% in patients with PAH.⁷ Patients who smoke may receive more than 2.5 mg per dose to match the therapeutic plasma concentration in non-smokers, and when patients stop smoking, practitioners should consider reducing the dose.⁷

Concomitant use of strong CYP or P-gp/BCRP inhibitors (e.g. ritonavir, ketoconazole) will increase drug exposure, so an initial dose of 0.5 mg three times daily should be considered, as opposed to the normal 1 mg initiation dose.⁷ On the other hand, strong CYP3A inducers such as St. John’s Wort or rifampin will decrease the exposure so a dose increase should be considered.⁷ Antacids (i.e. magnesium hydroxide and aluminum hydroxide) will decrease the absorption of the drug and should not be taken within an hour of taking riociguat (Adempas^®).⁷

Absolute contraindications to consider when prescribing and dispensing the agent include pregnancy, and co-administration of nitrates, nitric oxide (NO) donors, and PDEIs (specific and non-specific). Riociguat (Adempas^®) is pregnancy Category X, which means that the drug will almost certainly cause fetal abnormalities and should not be used in pregnant women because “the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.”⁹ Because it is Category X, the drug has a risk evaluation and mitigation strategies (REMS) program in place. “The FDA Amendments Act of 2007 gave FDA the authority to require a REMS from manufacturers to ensure that the benefits of a drug or biological product outweigh its risks.”⁸ All patients who are female have to enroll in the REMS program regardless of their reproductive potentials. ⁷ Prescribers and pharmacies also must enroll in the program to prescribe and dispense the medication. Patients who have reproductive potential must follow a strict requirement for contraceptives as outlined by the medication guide, and must also take a pregnancy test each month from the start of therapy until one month after discontinuation. ⁷

In studies such as PATENT-1, serious adverse effects shown were hypotension and bleeding.¹¹ If the patient cannot tolerate the hypotensive effects, the dose should be reduced. ⁷ On the other hand, riociguat (Adempas^®) did not cause priapism (a painful erection not associated with sexual stimulation),¹²  blue vision, or hearing loss that are usually associated with PDE-5 inhibitors (e.g. Sildenafil (Revatio^®)) due to their selectivity for PDE-5 and PDE-6. Patients who are currently taking PDE-5 inhibitors who do not like the aforementioned adverse effects may consider using riociguat (Adempas^®) for its FDA approved indications.

At $100/tablet, riociguat (Adempas^®) certainly is not cheap. The cost of treatment is $108,000/year; however, Bayer AG does offer a co-pay support program, which may cover up to 100% of the co-pay in some cases.¹³

For many who have failed other therapies and for whom operations were fruitless, riociguat (Adempas^®) may offer some relief for both pre-treated and treatment naïve patients.¹¹ Currently the agent has limited indication, limited access, high price, and its pregnancy Category X, and is not the mainstay of the market. However, the medication may suit those who find the other therapies ineffective or their side effects bothersome.

 

SOURCES:

1. U.S. Food and Drug administration. News & Events. FDA Website. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm370866.htm Updated October 8^th, 2013. Accessed February 9^th, 2014.
2. National Heart, Lung, and Blood Institute. What is Pulmonary Hypertension? National Institute of Health. http://www.nhlbi.nih.gov/health/health-topics/topics/pah. Accessed February 9^th, 2014.
3. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. J Am Coll Cardiol. 2009;53:1573-619.
4. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30:2493-2537.
5. Mathier MA. The classification of pulmonary arterial hypertension. Medscape Multispecialty. http://www.medscape.org/viewarticle/544175. 2006. Accessed ebruary 27^th, 2014.
6. Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP Evidence-Based Clinical Practice Guidelines. Introduction. Chest. 2004;126:7S-10S. http://journal.publications.chestnet.org/issue.aspx?issueid=22012. Accessed February 27^th, 2014.
7. Adempas® [package insert]. Barmen, Germany: Bayer AG; 2013.
8. Lexi-Comp Online^TM , Riociguat: Lexi-Drugs Online^TM. Hudson, Ohio: Lexi-Comp, Inc.; February 9^th, 2014.
9. Chemical Hazards Emergency Medical Managment. FDA Pregnancy Categories. U.S. Department of Health & Human Services. http://chemm.nlm.nih.gov/pregnancycategories.htm. Accessed February 9^th, 2014.
10. U.S. Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm111350.htm. Accessed February 14th, 2014.
11. Ghofrani H, Galie N, Grimminger F, et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2013;369;4: 330-40.
12. American Urological Association. Priapism. American Urological Association. https://www.auanet.org/education/guidelines/priapism.cfm. Accessed February 9^th, 2014.
13. Bayer AG. Adempas®: Aim Patient Support Program. Bayer AG. http://www.adempas-us.com/aim-patient-support-program/. Accessed February 9^th, 2014.

[pubmed_related keyword1=”riociguat” keyword2=”pulmonary” keyword3=”hypertension”]

Published by Rho Chi Post