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| Pronunciation | /pɪˈtɒlɪsənt/ pi-TOL-i-sənt |
| Trade names | Wakix, Ozawade |
| Other names | Tiprolisant; Ciproxidine; BF2.649 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a619055 |
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| Routes of administration | By mouth |
| Drug class | HistamineH3 receptorinverse agonist |
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| Eliminationhalf-life | 10–12 hours |
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| Formula | C17H26ClNO |
| Molar mass | 295.85 g·mol−1 |
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Pitolisant, sold under the brand nameWakix among others, is amedication used for the treatment ofexcessive daytime sleepiness in adults withnarcolepsy.[3] It is aninverse agonist of thehistamine H3 receptor.[3] It represents the first commercially available medication in its class, so that the U.S.Food and Drug Administration (FDA) declares it afirst-in-class medication.[7][8] Pitolisant enhances the activity of histaminergicneurons in the brain that function to improve a person's wakefulness.[9]It was approved by theEuropean Medicines Agency (EMA) in March 2016 for narcolepsy with or withoutcataplexy, and for excessive daytime sleepiness by the FDA in August 2019.[10] The most common side effects include difficulty sleeping, nausea, and feeling worried.[11]
Pitolisant isindicated in adults for the treatment ofnarcolepsy.[3][4] Narcolepsy is a chronicsleep disorder that causes overwhelming daytime drowsiness.[4] Pitolisant is also indicated to improve alertness and reduce excessive daytime sleepiness in adults withobstructive sleep apnea.[5][12]
The most common side effects includeinsomnia,headache,nausea,anxiety,irritability,dizziness,depression,tremor,sleep disorders,tiredness,vomiting,vertigo,dyspepsia, andheartburn.[4] Rare but serious side effects are abnormalweight loss andspontaneous abortion.[4]
Pitolisant is an inverse agonist of thehistamine H3 autoreceptor. The H3 autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine synthesis and release upon binding to endogenous histamine.[13] By preventing the binding of endogenous histamine at the H3, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.[14]
Pitolisant is a drug that belongs to the class ofcentral nervous system (CNS)stimulants.[15][16][17][18] Pitolisant is also considered aeugeroic, which means that it promotes wakefulness and alertness. Eugeroics are different from traditional CNS stimulants such asamphetamine in that they have fewer side effects and lower abuse potential. Pitolisant is the first eugeroic drug that acts by blocking the histamine H3 autoreceptor, which increases the activity of histamine neurons in the brain. Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.[19][20][21]
| Target | Ki | Activity |
|---|---|---|
| H3 | 150 nM | Inverse agonist |
| σ1 | <10 nM | Agonist |
| σ2 | 52 nM | Antagonist |
| D3 | 382 nM | Antagonist |
| 5-HT2A | 544 nM | Antagonist |
Pitolisant has been demonstrated to exhibit high affinity forsigma-1 andsigma-2 receptors, as well as moderate affinity for5-HT2A andD3 receptors. There exist conflicting findings relating the intrinsic activity of pitolisant at the 5-HT2A receptor.[23]
Pharmacokinetics
Pitolisant is readily absorbed when takenby mouth and reaches peak blood concentrations approximately 3 hours after administration. The biological half-life of Pitolisant ranges from 10 to 12 hours.[14]
Pitolisant is marketed in the European Union by Bioprojet Pharma.[4] It was approved for medical use in the European Union in March 2016 by theEuropean Medicines Agency (EMA).[10][4]
The U.S.Food and Drug Administration (FDA) approved pitolisant for excessive daytime sleepiness in participants with narcolepsy based primarily on evidence from two trials (Trial 1/NCT01067222, Trial 2/NCT01638403).[11] An additional trial (Trial 3/NCT01800045), in which participants with a different type of narcolepsy were exposed to the same dose of pitolisant, was used to add data for evaluation of side effects.[11] The trials were conducted in Europe and South America.[11]
The two primary trials enrolled adults with narcolepsy and excessive daytime sleepiness.[11] Participants received pitolisant, placebo, or an approved drug for narcolepsy for eight weeks.[11] For participants receiving pitolisant, the dose could be increased during the first three weeks but had to remain the same for the next five weeks.[11] Neither the participants nor the healthcare providers knew which treatment was being given during the trial.[11]
The benefit of pitolisant was evaluated by comparing changes in daytime sleepiness during the trial between pitolisant- and placebo-treated participants.[11] To measure the daytime sleepiness, the investigators used a scale called theEpworth Sleepiness Scale (ESS).[11] The ESS asks participants to rate the likelihood that they would fall asleep while doing eight daily activities (such as sitting and reading or watching television).[11] Participants rate each item from zero (would never doze) to three (high chance of dozing).[11]
Pitolisant was approved by the FDA in August 2019.[10][11] It was grantedorphan drug designation for the treatment ofnarcolepsy,[24]fast track designation for the treatment ofexcessive daytime sleepiness andcataplexy in people with narcolepsy, andbreakthrough therapy designation for the treatment of cataplexy in people with narcolepsy.[25]
Pitolisant is approved in the European Union and the United States to treat narcolepsy, and is not a controlled substance in these countries.[failed verification] Still, long-term studies comparing the effectiveness and tolerability of pitolisant withmodafinil orsodium oxybate are lacking.[failed verification] Pitolisant, the only non-controlled anti-narcoleptic drug in the US,[21] has shown minimal abuse risk in studies.[21][26]
This article incorporates text from this source, which is in thepublic domain.
