New Drugs in Pulmonary Arterial Hypertension
Most Recent Therapeutic Additions
The newest drug classes for PAH include the oral prostacyclin receptor agonist selexipag and the soluble guanylate cyclase stimulator riociguat, both representing first-in-class mechanisms that expand treatment options beyond traditional prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. 1, 2
Selexipag (Prostacyclin Receptor Agonist)
- Selexipag is an oral prostacyclin receptor agonist approved to delay disease progression and reduce the risk of hospitalization for PAH 2
- Starting dose is 200 mcg twice daily, with weekly increases of 200 mcg twice daily up to a maximum of 1,600 mcg twice daily based on tolerability 2
- This represents a significant advancement as it provides prostacyclin pathway activation without the need for continuous infusion or frequent inhalation 1, 2
- Most common adverse effects (≥5%) include headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing—all attributable to prostacyclin-mediated vasodilation 2
- Contraindicated with strong CYP2C8 inhibitors; requires dose reduction to once daily with moderate CYP2C8 inhibitors like clopidogrel 2
Riociguat (Soluble Guanylate Cyclase Stimulator)
- Riociguat is the first and only soluble guanylate cyclase stimulator approved for PAH, offering a dual mechanism: direct sGC stimulation independent of nitric oxide and sensitization of sGC to endogenous NO 1, 3, 4
- Dosing starts at 0.5-1.0 mg every 8 hours, increasing by 0.5 mg every 2 weeks as tolerated to a maximum of 2.5 mg three times daily 1
- This drug class targets the nitric oxide-soluble guanylate cyclase-cyclic GMP pathway through a mechanism distinct from PDE5 inhibitors 3, 5
- Riociguat is also the only medical therapy approved for chronic thromboembolic pulmonary hypertension (CTEPH) in patients who are inoperable or have persistent/recurrent disease after pulmonary endarterectomy 4, 5, 6
- Adverse events are primarily vasodilatory in nature, with potential for serious bleeding and fetal harm; contraindicated in pregnancy 4
Oral Treprostinil (Extended Prostacyclin Option)
- Oral treprostinil provides an alternative route for prostacyclin pathway activation, starting at 0.25 mg twice daily or 0.125 mg three times daily, with gradual titration every 3-4 days 1
- This expands the delivery options for treprostinil beyond subcutaneous, intravenous, and inhaled routes 1
Contemporary Combination Therapy Approach
- For WHO functional class III or IV patients remaining symptomatic on monotherapy with an endothelin receptor antagonist or PDE5 inhibitor, addition of inhaled treprostinil is recommended to improve 6-minute walk distance 1
- The optimal dose of inhaled treprostinil may require titration up to 9 inhalations (54 mcg) every 6 hours 1
- Current treatment paradigm emphasizes combination drug therapy targeting multiple biological pathways (such as combining endothelin antagonists with PDE5 inhibitors), which has improved 5-year survival from 34% in 1991 to more than 60% in 2015 6
Critical Prescribing Considerations
- Strong CYP2C8 inhibitors are contraindicated with selexipag; moderate CYP2C8 inhibitors require dose reduction to once daily 2
- CYP2C8 inducers like rifampin decrease exposure to selexipag's active metabolite and may require doubling the dose 2
- Patients with moderate hepatic impairment require modified dosing: selexipag starting dose of 200 mcg once daily with weekly increases 2
- Avoid selexipag in severe hepatic impairment 2
- All newer PAH therapies maintain the same pregnancy contraindications (category X) as established agents like bosentan, ambrisentan, macitentan, and riociguat 1