Peringatan Keamanan

Symptoms of pitolisant overdose may include headache, insomnia, irritability, nausea and abdominal pain. In case of overdose, hospitalisation and monitoring of the vital functions are recommended. There is no clearly identified antidote.L1471

After 1 month in mice, 6 months in rats and 9 months in monkeys, no adverse effect level (NOAEL) were 75, 30 and 12 mg/kg/day, p.o., respectively.L1471 Pitolisant was not found to be genotoxic in Ames test nor carcinogenic in mouse and rat carcinogenicity studies. In rabbit and rat teratogenicity studies, maternally high toxic doses of pitolisant sperm morphology abnormalities and decreased motility without any significant effect on fertility indexes in male rats. It also decreased the percentage of live conceptuses and increased post-implantation loss in female rats. A delay in post-natal development was observed.L1471

Pitolisant

DB11642

small molecule approved investigational

Deskripsi

Pitolisant is a selective antagonist or inverse agonist of the histamine H3 receptor used to treat type 1 or 2 narcolepsy.L8063 Narcolepsy is a chronic neurological disorder that affects 1 in 2,000 individuals and is characterized by excessive daytime sleepiness, abnormal REM sleep manifestations, sleep paralysis and hypnagogic hallucinations.A32025 About 60-70% of patients with narcolepsy experience cataplexy, which is a sudden loss of muscle tone triggered by positive or negative emotions.A32022 Histaminergic neuron signalling in the brain plays a role in maintaining wakefulness; by blocking histamine autoreceptors, pitolisant enhances the activity of histaminergic neurons, as well as increasing the signalling of other neurotransmitters in the brain.

In a European clinical trial of adult patients with narcolepsy, there was a reduction in the Epworth Sleepiness Scale (ESS) score from pitolisant therapy compared to placebo.A32024 The therapeutic effectiveness of pitolisant was comparable to that of modafinil.A32024 Pitolisant therapy was also effective in treating refractory sleepiness in adolescent patients with narcolepsy, where it decreased ESS score and increased the mean sleep onset latency.A32023 Adolescent patients with cataplexy also experienced a slight improvement in the frequency and severity of symptoms A32023; however, the safety of use in adolescent or paediatric patients have not been established with pitolisant. Commonly marketed under the trade name Wakix, oral pitolisant was approved by the EMA in 2016 A183062 for the treatment of narcolepsy with or without cataplexy. FDA approved the use of pitolisant in 2019 for excessive daytime sleepiness (EDS) associated with narcolepsy in adults.L8063

Struktur Molekul 2D

Berat 295.85
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Pitolisant has a plasma half-life of 10-12 hours.[L1471] After administration of a single dose of 35.6 mg, the median half-life of pitolisant was approximately 20 hours.[L8063]
Volume Distribusi Following single and multiple oral dosing of pitolisant to healthy male adults at doses between 1 and 240 mg, the apparent volume of distribution (V/F) ranges from 1100 to 2825 L. Pitolisant is thought to be equally distributed between red blood cells and plasma.[L1471] Following intravenous administration of pitolisant in rats and monkeys, the apparent Vd at steady-state was approximately 10-fold greater than total body water. Pitolisant crosses the blood-brain barrier and placenta, and was found in milk in rats.
Klirens (Clearance) The apparent oral clearance (CL/F) of pitolisant was 43.9 L/hr following a single dose of 35.6 mg.[L8063] The clearance rate is expected to be lower with increasing age.

Absorpsi

Pitolisant is rapidly and well absorbed following oral administration, resulting in the drug being 90% absorbed.L8063 In healthy individuals receiving an oral dose of 20 mg, the Cmax was approximately 30 ng/mL.A32025 Following oral administration of pitolisant 35.6 mg once daily, the mean steady state Cmax and AUC were 73 ng/mL and 812 ngxhr/mL, respectively.L8063 The Tmax was typically reached approximately 3 hours following administration.L1471 Following repeated dosing, the steady-state plasma concentration is achieved after 5-6 days of administration but the inter-individual variability in the time to reach steady-state is reported to be high.L1471 The absolute bioavailability of pitolisant has not been determined.

Metabolisme

Pitolisant is primarily metabolized by CYP2D6 and to a lesser extent by CYP3A4 in the liver. The major non-conjugated metabolites are BP2.941 (piperidine N-oxide) and BP2.951 (5-aminovaleric acid).L1471 Metabolites can further undergo conjugation with glycine or glucuronic acid, and oxidation to a minimal extent. Most metabolites of pitolisant do not retain considerable pharmacological activities.L8063 Several conjugated metabolites were also identified; the major conjugated inactive metabolite was a glycine conjugate of the acid metabolite of O-dealkylated desaturated pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant.L1471 Due to its extensive metabolism in the liver, the systemic exposure of pitolisant thus adverse events of the drug may be elevated in case of compromised liver function. The dosage adjustments for pitolisant is advised in patients with moderate hepatic impairment.L8063

Rute Eliminasi

Following hepatic metabolism, about 63% of total elimination occurs via renal excretion into the urine as an inactive non-conjugated metabolite BP2.951 and a glycine conjugated metabolite.L1471 About 25% of the total dose administered is excreted through expired air as metabolites, and a small fraction (<3%) of drug can be recovered in faeces.L1471

Interaksi Makanan

2 Data
  • 1. Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of pitolisant. Dose adjustment may be necessary for co-administration.
  • 2. Take with or without food. A high-fat meal had no clinically significant effects on drug pharmacokinetics.

Interaksi Obat

1765 Data
Benzylpenicilloyl polylysine Pitolisant may decrease effectiveness of Benzylpenicilloyl polylysine as a diagnostic agent.
Betahistine The therapeutic efficacy of Betahistine can be decreased when used in combination with Pitolisant.
Atomoxetine The metabolism of Atomoxetine can be decreased when combined with Pitolisant.
Ifosfamide The metabolism of Ifosfamide can be increased when combined with Pitolisant.
Perampanel The metabolism of Perampanel can be increased when combined with Pitolisant.
R,S-Warfarin alcohol The metabolism of R,S-Warfarin alcohol can be increased when combined with Pitolisant.
S,R-Warfarin alcohol The metabolism of S,R-Warfarin alcohol can be increased when combined with Pitolisant.
Amphetamine Amphetamine may decrease the sedative activities of Pitolisant.
Pseudoephedrine Pseudoephedrine may decrease the sedative activities of Pitolisant.
Diethylpropion Diethylpropion may decrease the sedative activities of Pitolisant.
Mephentermine Mephentermine may decrease the sedative activities of Pitolisant.
MMDA MMDA may decrease the sedative activities of Pitolisant.
Midomafetamine Midomafetamine may decrease the sedative activities of Pitolisant.
2,5-Dimethoxy-4-ethylamphetamine 2,5-Dimethoxy-4-ethylamphetamine may decrease the sedative activities of Pitolisant.
4-Bromo-2,5-dimethoxyamphetamine 4-Bromo-2,5-dimethoxyamphetamine may decrease the sedative activities of Pitolisant.
Tenamfetamine Tenamfetamine may decrease the sedative activities of Pitolisant.
Chlorphentermine Chlorphentermine may decrease the sedative activities of Pitolisant.
Methylenedioxyethamphetamine Methylenedioxyethamphetamine may decrease the sedative activities of Pitolisant.
Dextroamphetamine Dextroamphetamine may decrease the sedative activities of Pitolisant.
Metamfetamine Metamfetamine may decrease the sedative activities of Pitolisant.
Iofetamine I-123 Iofetamine I-123 may decrease the sedative activities of Pitolisant.
Ritobegron Ritobegron may decrease the sedative activities of Pitolisant.
Mephedrone Mephedrone may decrease the sedative activities of Pitolisant.
Methoxyphenamine Methoxyphenamine may decrease the sedative activities of Pitolisant.
Gepefrine Gepefrine may decrease the sedative activities of Pitolisant.
2,5-Dimethoxy-4-ethylthioamphetamine 2,5-Dimethoxy-4-ethylthioamphetamine may decrease the sedative activities of Pitolisant.
Lisdexamfetamine The serum concentration of dextroamphetamine, an active metabolite of Lisdexamfetamine, can be increased when used in combination with Pitolisant.
Phendimetrazine Phendimetrazine may decrease the sedative activities of Pitolisant.
Erlotinib The serum concentration of Erlotinib can be decreased when it is combined with Pitolisant.
Penbutolol The metabolism of Penbutolol can be decreased when combined with Pitolisant.
Arotinolol The metabolism of Arotinolol can be decreased when combined with Pitolisant.
Atenolol The metabolism of Atenolol can be decreased when combined with Pitolisant.
Remoxipride The metabolism of Remoxipride can be decreased when combined with Pitolisant.
Piperazine The metabolism of Piperazine can be decreased when combined with Pitolisant.
Nicergoline The metabolism of Nicergoline can be decreased when combined with Pitolisant.
Minaprine The metabolism of Minaprine can be decreased when combined with Pitolisant.
Alprenolol The metabolism of Alprenolol can be decreased when combined with Pitolisant.
Phenformin The metabolism of Phenformin can be decreased when combined with Pitolisant.
Idarubicin The metabolism of Idarubicin can be decreased when combined with Pitolisant.
Bevantolol The metabolism of Bevantolol can be decreased when combined with Pitolisant.
Practolol The metabolism of Practolol can be decreased when combined with Pitolisant.
Aprindine The metabolism of Aprindine can be decreased when combined with Pitolisant.
4-Methoxyamphetamine The metabolism of 4-Methoxyamphetamine can be decreased when combined with Pitolisant.
Repinotan The metabolism of Repinotan can be decreased when combined with Pitolisant.
Tafenoquine The metabolism of Tafenoquine can be decreased when combined with Pitolisant.
Bufuralol The metabolism of Bufuralol can be decreased when combined with Pitolisant.
Enclomiphene The metabolism of Enclomiphene can be decreased when combined with Pitolisant.
Benzyl alcohol The metabolism of Benzyl alcohol can be decreased when combined with Pitolisant.
Bopindolol The metabolism of Bopindolol can be decreased when combined with Pitolisant.
Levobetaxolol The metabolism of Levobetaxolol can be decreased when combined with Pitolisant.
Landiolol The metabolism of Landiolol can be decreased when combined with Pitolisant.
Bucindolol The metabolism of Bucindolol can be decreased when combined with Pitolisant.
Esatenolol The metabolism of Esatenolol can be decreased when combined with Pitolisant.
Cloranolol The metabolism of Cloranolol can be decreased when combined with Pitolisant.
Mepindolol The metabolism of Mepindolol can be decreased when combined with Pitolisant.
Epanolol The metabolism of Epanolol can be decreased when combined with Pitolisant.
Tertatolol The metabolism of Tertatolol can be decreased when combined with Pitolisant.
Butyrfentanyl The metabolism of Butyrfentanyl can be decreased when combined with Pitolisant.
Bicifadine The metabolism of Bicifadine can be decreased when combined with Pitolisant.
5-methoxy-N,N-dimethyltryptamine The metabolism of 5-methoxy-N,N-dimethyltryptamine can be decreased when combined with Pitolisant.
Nadolol The metabolism of Nadolol can be decreased when combined with Pitolisant.
Debrisoquine The metabolism of Debrisoquine can be decreased when combined with Pitolisant.
Labetalol The metabolism of Labetalol can be decreased when combined with Pitolisant.
Perphenazine The metabolism of Perphenazine can be decreased when combined with Pitolisant.
Moclobemide The metabolism of Moclobemide can be decreased when combined with Pitolisant.
Sparteine The metabolism of Sparteine can be decreased when combined with Pitolisant.
Dexfenfluramine The metabolism of Dexfenfluramine can be decreased when combined with Pitolisant.
Cimetidine The risk or severity of adverse effects can be increased when Pitolisant is combined with Cimetidine.
Pindolol The metabolism of Pindolol can be decreased when combined with Pitolisant.
Tranylcypromine The metabolism of Pitolisant can be decreased when combined with Tranylcypromine.
Sulfaphenazole The metabolism of Pitolisant can be decreased when combined with Sulfaphenazole.
Phenylbutyric acid The metabolism of Pitolisant can be decreased when combined with Phenylbutyric acid.
Ritanserin The metabolism of Pitolisant can be decreased when combined with Ritanserin.
Rhein The metabolism of Pitolisant can be decreased when combined with Rhein.
Metoprolol The metabolism of Pitolisant can be decreased when combined with Metoprolol.
Duloxetine The metabolism of Pitolisant can be decreased when combined with Duloxetine.
Ticlopidine The metabolism of Ticlopidine can be decreased when combined with Pitolisant.
Icosapent The risk or severity of adverse effects can be increased when Icosapent is combined with Pitolisant.
Mesalazine Mesalazine may decrease the excretion rate of Pitolisant which could result in a higher serum level.
Indomethacin The risk or severity of adverse effects can be increased when Indomethacin is combined with Pitolisant.
Nabumetone The risk or severity of adverse effects can be increased when Nabumetone is combined with Pitolisant.
Ketorolac The risk or severity of adverse effects can be increased when Ketorolac is combined with Pitolisant.
Tenoxicam The risk or severity of adverse effects can be increased when Tenoxicam is combined with Pitolisant.
Celecoxib The risk or severity of adverse effects can be increased when Celecoxib is combined with Pitolisant.
Tolmetin The risk or severity of adverse effects can be increased when Tolmetin is combined with Pitolisant.
Rofecoxib The risk or severity of adverse effects can be increased when Rofecoxib is combined with Pitolisant.
Piroxicam The risk or severity of adverse effects can be increased when Piroxicam is combined with Pitolisant.
Fenoprofen The risk or severity of adverse effects can be increased when Fenoprofen is combined with Pitolisant.
Valdecoxib The risk or severity of adverse effects can be increased when Valdecoxib is combined with Pitolisant.
Diclofenac The risk or severity of adverse effects can be increased when Diclofenac is combined with Pitolisant.
Sulindac The risk or severity of adverse effects can be increased when Sulindac is combined with Pitolisant.
Flurbiprofen The risk or severity of adverse effects can be increased when Flurbiprofen is combined with Pitolisant.
Etodolac The risk or severity of adverse effects can be increased when Etodolac is combined with Pitolisant.
Mefenamic acid The risk or severity of adverse effects can be increased when Mefenamic acid is combined with Pitolisant.
Naproxen The risk or severity of adverse effects can be increased when Naproxen is combined with Pitolisant.
Sulfasalazine The risk or severity of adverse effects can be increased when Sulfasalazine is combined with Pitolisant.
Phenylbutazone The risk or severity of adverse effects can be increased when Phenylbutazone is combined with Pitolisant.
Meloxicam The risk or severity of adverse effects can be increased when Meloxicam is combined with Pitolisant.
Carprofen The risk or severity of adverse effects can be increased when Carprofen is combined with Pitolisant.
Diflunisal The risk or severity of adverse effects can be increased when Diflunisal is combined with Pitolisant.

Target Protein

Histamine H3 receptor HRH3
Voltage-gated inwardly rectifying potassium channel KCNH2 KCNH2

Referensi & Sumber

Artikel (PubMed)
  • PMID: 28490912
    Calik MW: Update on the treatment of narcolepsy: clinical efficacy of pitolisant. Nat Sci Sleep. 2017 Apr 26;9:127-133. doi: 10.2147/NSS.S103462. eCollection 2017.
  • PMID: 22356925
    Inocente C, Arnulf I, Bastuji H, Thibault-Stoll A, Raoux A, Reimao R, Lin JS, Franco P: Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness. Clin Neuropharmacol. 2012 Mar-Apr;35(2):55-60. doi: 10.1097/WNF.0b013e318246879d.
  • PMID: 24107292
    Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, Lehert P, Ding CL, Lecomte JM, Schwartz JC: Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013 Nov;12(11):1068-75. doi: 10.1016/S1474-4422(13)70225-4. Epub 2013 Oct 7.
  • PMID: 21615387
    Schwartz JC: The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol. 2011 Jun;163(4):713-21. doi: 10.1111/j.1476-5381.2011.01286.x.
  • PMID: 30214155
    Romigi A, Vitrani G, Lo Giudice T, Centonze D, Franco V: Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy. Drug Des Devel Ther. 2018 Aug 30;12:2665-2675. doi: 10.2147/DDDT.S101145. eCollection 2018.
  • PMID: 29802412
    Kotanska M, Kuder KJ, Szczepanska K, Sapa J, Kiec-Kononowicz K: The histamine H3 receptor inverse agonist pitolisant reduces body weight in obese mice. Naunyn Schmiedebergs Arch Pharmacol. 2018 Aug;391(8):875-881. doi: 10.1007/s00210-018-1516-2. Epub 2018 May 25.
  • PMID: 28941245
    Ligneau X, Shah RR, Berrebi-Bertrand I, Mirams GR, Robert P, Landais L, Maison-Blanche P, Faivre JF, Lecomte JM, Schwartz JC: Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies. Br J Pharmacol. 2017 Dec;174(23):4449-4463. doi: 10.1111/bph.14047. Epub 2017 Oct 19.

Contoh Produk & Brand

Produk: 12 • International brands: 0
Produk
  • Ozawade
    Tablet, film coated • 4.45 mg • Oral • EU • Approved
  • Ozawade
    Tablet, film coated • 17.8 mg • Oral • EU • Approved
  • Ozawade
    Tablet, film coated • 17.8 mg • Oral • EU • Approved
  • Ozawade
    Tablet, film coated • 4.45 mg • Oral • EU • Approved
  • Wakix
    Tablet • 5 mg • Oral • Canada • Approved
  • Wakix
    Tablet • 20 mg • Oral • Canada • Approved
  • Wakix
    Tablet, film coated • 4.45 mg/1 • Oral • US • Approved
  • Wakix
    Tablet, film coated • 17.8 mg/1 • Oral • US • Approved
Menampilkan 8 dari 12 produk.

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