Selexipag

Mechanism of action

◎Prostacyclin receptor (IP receptor)Selexipag

ⓘ The figure shows MRE-269, the active metabolite of selexipag, bound to the human prostacyclin (IP) receptor with its G protein (cryo-EM).

Selexipag is a prodrug that is chemically different from prostacyclin. Carboxylesterase 1 hydrolyses it to an active metabolite that is much more potent at the prostacyclin (IP) receptor. Activation of this receptor raises cyclic AMP in pulmonary vascular smooth muscle, which relaxes the vessels. This oral route avoids the continuous infusions needed for epoprostenol.

1. Selexipag is hydrolysed to a more potent active metabolite
2. The metabolite activates the prostacyclin (IP) receptor
3. Cyclic AMP rises and pulmonary arteries relax
4. PAH progression and hospitalisation are delayed

Indications

• Pulmonary arterial hypertension (WHO group 1) in adults, to delay disease progression and reduce PAH hospitalisation Pulmonary hypertension and cor pulmonale →

Adverse effects

Common

• Headache and flushing
• Jaw pain, myalgia and pain in the limbs
• Nausea, vomiting and diarrhoea
• Decreased appetite and rash

Contraindications

• Strong CYP2C8 inhibitors such as gemfibrozil
• Hypersensitivity to selexipag
• Severe hepatic impairment is avoided

Key interactions

Gemfibrozil (strong CYP2C8 inhibitor)

Much higher active-metabolite exposure; contraindicated

Moderate CYP2C8 inhibitors (clopidogrel, deferasirox, teriflunomide)

Higher active-metabolite exposure; dosing is reduced to once daily

Rifampicin (CYP2C8 and UGT inducer)

Lower active-metabolite exposure; the dose may need increasing

What is monitored

• Tolerance during the gradual dose build-up (headache, jaw pain, nausea)
• Breathlessness and signs of pulmonary oedema
• Thyroid function if symptoms suggest hyperthyroidism
• Liver disease (dose regimen)

Administration and safety

• Oral tablets swallowed whole, not split, chewed or crushed
• The dose is built up gradually, at most once a week, to the highest tolerated
• Taking it with food may make it easier to tolerate

Pregnancy and breastfeeding

There are no adequate human studies; animal studies did not show relevant fetal harm. Pulmonary hypertension itself carries high risk in pregnancy, and use is decided with the specialist.

Nursing care

• Teach that headache, jaw pain and flushing are expected during the build-up and tend to ease
• Teach not to stop it without medical advice
• Review the medicine list for gemfibrozil, clopidogrel, deferasirox, teriflunomide and rifampicin
• Teach to report breathlessness, rapid breathing or dizziness at once

Pharmacokinetics

Absorption

Oral; absolute bioavailability about 49%; food slows absorption but not total exposure

Distribution

Highly bound to plasma proteins (about 99%)

Metabolism

Hydrolysed by carboxylesterase 1 to the active metabolite, then oxidised by CYP2C8 and to a lesser extent CYP3A4

Elimination

Mainly in faeces

Half-life

Parent short (under about 2.5 hours); active metabolite about 6 to 13.5 hours

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Connections

← Back to the class: Pulmonary arterial hypertension drugs (endothelin receptor antagonists and prostacyclins)

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: DailyMed - SELEXIPAG tablet, film coated SELEXIPAG TITRATION PACK- selexipag kit (DailyMed (U.S. National Library of Medicine), 2026); Selexipag: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); RCSB PDB - 8X79: MRE-269 bound Prostacyclin Receptor G protein complex (RCSB Protein Data Bank, 2024); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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Representative model, for educational purposes only.