Selexipag, sold under the brand name Uptravi, is a medication developed by

Actelion Actelion is a pharmaceuticals and biotechnology company established in December 1997, headquartered in Allschwil near Basel, Switzerland. Actelion focuses on the manufacture of drugs that treat rare diseases and orphan diseases. Some of the dru ...

for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

, ACT-333679 (or MRE-269, the free

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

), are

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

s of the

prostacyclin receptor The Prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, ...

, which leads to vasodilation in the pulmonary circulation. It is taken by mouth or administered intravenously.

Contraindications

In Europe, use of selexipag together with strong inhibitors of the liver enzyme

CYP2C8 Cytochrome P4502C8 (abbreviated CYP2C8), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-cha ...

, such as

gemfibrozil Gemfibrozil, sold under the brand name Lopid among others, is a medication used to treat abnormal blood lipid levels. It is generally less preferred than statins. Use is recommended together with dietary changes and exercise. It is unclear if ...

, is contraindicated because it increases concentrations of selexipag twofold, and its active metabolite 11-fold, potentially leading to more adverse effects.

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.

Pharmacology

Mechanism of action

Selexipag and its

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 Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...

and inhibition of platelet aggregation, all beneficial in the treatment of pulmonary arterial hypertension.

Pharmacokinetics

Selexipag is quickly absorbed from the gut and

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

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 The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...

. 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 Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

, namely to albumin and

alpha-1-acid glycoprotein Orosomucoid (ORM) or alpha-1-acid glycoprotein (''α1AGp'', ''AGP'' or ''AAG'') is an acute phase protein found in plasma. It is an alpha-globulin glycoprotein and is modulated by two polymorphic genes. It is synthesized primarily in hepatocyt ...

to equal amounts. The liver enzymes

and, to a lesser extent,

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

hydroxylate In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemistry, chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH gr ...

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.

History

The U.S. Food and Drug Administration (FDA) granted selexipag

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

status for PAH. It was approved by the FDA on 22 December 2015.New Drug Approved for Rare Lung Disorder. PPN. 23 Dec 2015
Has link to GRIPHON study results In Europe, the drug was approved in May 2016.

Society and culture

Economics

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

References

External links

* * {{Portal bar , Medicine Acetamides Drugs acting on the cardiovascular system Japanese brands Pyrazines Sulfonamides Isopropyl compounds Carboxamides Ethers