Selexipag

Clinical data
Trade names	Uptravi
Other names	ACT-293987, NS-304
License data	US DailyMed: Selexipag US FDA: Selexipag
Routes of administration	By mouth, intravenous
ATC code	B01AC27 (WHO)
Legal status
Legal status	US: ℞-only [1] EU: Rx-only
Pharmacokinetic data
Bioavailability	49%
Protein binding	99%
Metabolism	Activation by carboxylesterases, inactivation by CYP2C8 and others
Metabolites	ACT-333679, the free acid (active metabolite)
Elimination half-life	0.8–2.5 h (selexipag) and 6.2–13.5 h (ACT-333679)
Excretion	93% faeces
Identifiers
IUPAC name 2-{4-[(5,6-Diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide
CAS Number	475086-01-2
PubChem CID	9913767
IUPHAR/BPS	7552
DrugBank	DB11362
ChemSpider	8089417 Y
UNII	5EXC0E384L
KEGG	D09994 Y
ChEBI	CHEBI:90844 Y
ChEMBL	ChEMBL238804 Y
ECHA InfoCard	100.237.916
Chemical and physical data
Formula	C26H32N4O4S
Molar mass	496.63 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(C)N(CCCCOCC(=O)NS(=O)(=O)C)C1=CN=C(C(=N1)C2=CC=CC=C2)C3=CC=CC=C3
InChI InChI=1S/C26H32N4O4S/c1-20(2)30(16-10-11-17-34-19-24(31)29-35(3,32)33)23-18-27-25(21-12-6-4-7-13-21)26(28-23)22-14-8-5-9-15-22/h4-9,12-15,18,20H,10-11,16-17,19H2,1-3H3,(H,29,31)  Y Key:QXWZQTURMXZVHJ-UHFFFAOYSA-N
NY (what is this?)  (verify)

Selexipag, sold under the brand name Uptravi, is a medication developed by Actelion for the treatment of pulmonary arterial hypertension (PAH).^[1] Selexipag and its active metabolite, ACT-333679 (or MRE-269, the free carboxylic acid), are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation.^[2] It is taken by mouth or administered intravenously.^[1][3]

Contraindications

In Europe, use of selexipag together with strong inhibitors of the liver enzyme CYP2C8, such as gemfibrozil, is contraindicated because it increases concentrations of selexipag twofold, and its active metabolite 11-fold, potentially leading to more adverse effects.^[4]

Adverse effects

The adverse effects of selexipag are similar to those of intravenous prostacyclins used for pulmonary arterial hypertension. Common side effects include headache and jaw pain. An increased risk for hyperthyroidism has also been noted in people taking selexipag.^[5]

Pharmacology

Mechanism of action

ACT-333679, the active metabolite

Selexipag and its active metabolite ACT-333679 act on the prostacyclin receptor of lung tissue, with the latter being 37-fold more potent. They are selective for the prostacyclin receptor. Binding to this receptor leads to three major effects: increased vasodilation of the arteries, decreased cell proliferation and inhibition of platelet aggregation,^[5] all beneficial in the treatment of pulmonary arterial hypertension.

Pharmacokinetics

Selexipag is quickly absorbed from the gut and hydrolyzed in the intestines and the liver to ACT-333679 by carboxylesterases. Absolute bioavailability is about 49%, most likely because of a high first-pass effect. Highest concentrations in the blood plasma are reached after one to three hours for selexipag and after three to four hours for the active metabolite. When in the circulation, about 99% of both substances are bound to plasma proteins, namely to albumin and alpha-1-acid glycoprotein to equal amounts.^[5]

The liver enzymes CYP2C8 and, to a lesser extent, CYP3A4, hydroxylate and dealkylate the active substance, thereby inactivating it. Besides, ACT-333679 is glucuronidized by the enzymes UGT1A3 and UGT2B7. The terminal half-life of selexipag is 0.8 to 2.5 hours, that of the active metabolite is 6.2 to 13.5 hours.^[5]

History

The U.S. Food and Drug Administration (FDA) granted selexipag orphan drug status for PAH.^[6] It was approved by the FDA on 22 December 2015.^[6]

In Europe, the drug was approved in May 2016.^[5]

Society and culture

Economics

The expected price for the drug in the US is $160,000 to $170,000 per patient before rebates.^[7]