Identification

Name
Pitolisant
Accession Number
DB11642
Type
Small Molecule
Groups
Approved, Investigational
Description

Pitolisant is also known as 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine or BF2.649 [4]. It is a selective inverse agonist of the histamine H3 receptor that is used in the treatment of type 1 or 2 narcolepsy with or without cataplexy in adults. Narcolepsy is a chronic neurological disorder that that affects 1 in 2,000 individuals and is characterized by excessive daytime sleepiness, abnormal REM sleep manifestations, sleep paralysis and hypnagogic hallucinations [4]. About 60-70% of patients with narcolepsy experience cataplexy, which is a sudden loss of muscle tone triggered by positive or negative emotion [1]. As histaminergic signalling in neurons plays a role in maintaining wakefulness, pitolisant works by blocking histamine autoreceptors and enhancing the activity of brain histaminergic neurons [5].

In a European clinical trial of adult patients with narcolepsy, a reduction in the Epworth Sleepiness Scale (ESS) score was observed from pitolisant treatment compared to placebo [3]. The therapeutic effectiveness of pitolisant was comparable to that of Modafinil [3]. 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 [2]. Adolescent patients with cataplexy also experienced a slight improvement in the frequency and severity of symptoms [2], however the safety of use in adolescent or paediatric patients have not been established with pitolisant. Pitolisant is marketed by EMA under the trade name Wakix as oral tablets.

Structure
Thumb
Synonyms
Not Available
External IDs
BF-2.649 / BF-2649 / BF2.649
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
WakixTablet, film coated4.5 mgOralBioprojet Pharma2016-03-31Not applicableEu
WakixTablet, film coated18 mgOralBioprojet Pharma2016-03-31Not applicableEu
Categories
UNII
4BC83L4PIY
CAS number
362665-56-3
Weight
Average: 295.85
Monoisotopic: 295.1702922
Chemical Formula
C17H26ClNO
InChI Key
NNACHAUCXXVJSP-UHFFFAOYSA-N
InChI
InChI=1S/C17H26ClNO/c18-17-9-7-16(8-10-17)6-4-14-20-15-5-13-19-11-2-1-3-12-19/h7-10H,1-6,11-15H2
IUPAC Name
1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine
SMILES
ClC1=CC=C(CCCOCCCN2CCCCC2)C=C1

Pharmacology

Indication

Indicated in adults for the treatment of narcolepsy with or without cataplexy [5].

Associated Conditions
Pharmacodynamics

In patients with narcolepsy in presence or absence of cataplexy, treatment of pitolisant was associated with an improvement in the level and duration of wakefulness and daytime alertness assessed by objective measures of ability to sustain wakefulness (e.g. Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) Scores) and attention (e.g. Sustained Attention to Response Task (SART)) [5]. Pitolisant also improved the frequency and severity of narcolepsy-associated cataplexy [1]. Pitolisant acts as a blocker at hERG channels. In two dedicated QT studies, supra-therapeutic doses of pitolisant (3-6-times the therapeutic dose, that is 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10-13 ms) [5].

Mechanism of action

Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human histamine H3 receptor subtype [1]. Signalling of histaminergic neurons plays a key role in activating the arousal system with widespread projections to the whole brain [5] via activating orexin receptors [1]. Narcolepsy is characterized by insufficient neurotransmission by orexins, or hypocretins, which are excitatory peptides released by aminergic neurons from the lateral hypothalamus with widespread projections [4]. H3 receptors are autoreceptors that promote the re-uptake of histamine at synaptic terminals and attenuate further histamine release into the synapse [4]. By blocking H3 autoreceptors and increasing the levels of histamine transmitters at the synapse, pitolisant enhances the activity of brain histaminergic neurons and promotes wakefulness [5]. Inverse agonism of pitolisant at H3 receptors also leads to enhanced synthesis and release of endogenous histamine over the basal level [4].

Pitolisant is thought to bind to the antagonist binding site of H3 receptor, which is located within the trans-membrane core just below the extracellular loops. Piperidines forms a salt bridge with Glu206 in the membrane spanning segment and the hydroxyl of Tyr374 is H-bonded with the central oxygen of piperidine [4]. Pitolisant displays high selectivity for H3 receptors compared to other histamine receptor subtypes. Pitolisant also modulates acetylcholine, noradrenaline and dopamine release in the brain by increasing the levels of neurotransmitters but does not increase dopamine release in the stratal complex including nucleus accumbent [5].

TargetActionsOrganism
AHistamine H3 receptor
antagonist
inverse agonist
Human
NPotassium voltage-gated channel subfamily H member 2
blocker
Human
Absorption

Pitolisant is rapidly and well absorbed. Following oral administration of 20 mg in healthy individuals, the peak plasma concentration (Cmax) was approximately 30 ng/mL [4]. The Cmax is typically reached approximately 3 hours following administration [5]. Food intake significantly reduces the systemic exposure of pitolisant with a decrease in both AUC and Cmax [6]. Following repeated dosing, the steady-state plasma concentration is achieved after 5-6 days of administration leading to an increased serum level around 100% [5]. Inter individual variability is reported to be high [5]. The absolute bioavailability of pitolisant has not been determined [6].

Volume of distribution

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 [6]. Pitolisant is thought to be equally distributed between red blood cells and plasma [5]. Following intravenous administration of pitolisant in rats and monkeys, the apparent Vd at steady-state was approximately 10-fold greater than total body water [6]. Pitolisant crosses the blood-brain barrier and placenta, and was found in milk in rats [6].

Protein binding

Pitolisant exhibits high serum protein binding (>90%) [5].

Metabolism

Pitolisant undergoes hepatic CYP3A4- and CYP2D6-mediated metabolism to form major non-conjugated metabolites BP2.941 and BP2.951 , which are hydroxylated derivatives in several positions [5]. BP2.941 and BP2.951 can further be oxidized but oxidized metabolites of pitolisant such as BP1.2525 and BP1.2526 are only present to a minor extent [6]. Only BP1.2526 and BP1.2525 at a lesser extent have an affinity towards human H3 receptor [6]. The 5-aminovaleric acid is the major phase I inactive metabolite and is found in urine and serum, and its metabolism is mediated by CYP3A4 and CYP2D6 [5].

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 [5].

Route of elimination

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 [5]. 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 [5].

Half life

Pitolisant has a plasma half-life of 10-12 hours [5].

Clearance

The apparent clearance rate is expected to be lower with increasing age [6].

Toxicity

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 [5].

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 [5]. Pitolisant was not found to be genotoxic in Ames test nor carcinogenic in mouse and rat carcinogenicity studies [6]. 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 [5]. It also decreased the percentage of live conceptuses and increased post-implantation loss in female rats [5]. A delay in post-natal development was observed [5].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Pitolisant.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Pitolisant.
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine may decrease the sedative and stimulatory activities of Pitolisant.
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine may decrease the sedative and stimulatory activities of Pitolisant.
3,4-Methylenedioxyamphetamine3,4-Methylenedioxyamphetamine may decrease the sedative and stimulatory activities of Pitolisant.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Pitolisant.
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may decrease the sedative and stimulatory activities of Pitolisant.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Pitolisant.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Pitolisant.
5-androstenedioneThe metabolism of 5-androstenedione can be increased when combined with Pitolisant.
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:28490912]
  2. 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. [PubMed:22356925]
  3. 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. [PubMed:24107292]
  4. 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. [PubMed:21615387]
  5. Wakix, INN-Pitolisant - European Medicines Agency - Europa EU [Link]
  6. Wakix, INN-pitolisant - European Medicines Agency - Europa EU: Assessment report [Link]
External Links
ChemSpider
8123714
BindingDB
50247053
ChEBI
134709
ChEMBL
CHEMBL462605
Wikipedia
Pitolisant
ATC Codes
N07XX11 — Pitolisant

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers / Substance Abuse1
1CompletedTreatmentImpaired Renal Function1
2CompletedTreatmentExcessive Daytime Sleepiness / Obstructive Sleep Apnoea (OSA)1
2CompletedTreatmentExcessive Daytime Sleepiness / Parkinson's Disease (PD)1
2CompletedTreatmentSchizophrenic Disorders1
2RecruitingTreatmentNarcolepsy With Cataplexy / Narcolepsy Without Cataplexy1
2WithdrawnTreatmentAlcohol Abuse, Nervous System1
3CompletedTreatmentCataplexy / Excessive Daytime Sleepiness / Narcolepsy1
3CompletedTreatmentCataplexy / Excessive Daytime Sleepiness / Narcolepsy / Sleep disorders and disturbances1
3CompletedTreatmentCataplexy / Narcolepsy1
3CompletedTreatmentExcessive Daytime Sleepiness / Narcolepsy With Cataplexy1
3CompletedTreatmentExcessive Daytime Sleepiness / Obstructive Sleep Apnea (OSA)3
3CompletedTreatmentNarcolepsy1
3CompletedTreatmentParkinson's Disease (PD)2
3CompletedTreatmentTreatment of Excessive Daytime Sleepiness in Narcolepsy1
3WithdrawnTreatmentExcessive Daytime Sleepiness / Obstructive Sleep Apnea (OSA)1
Not AvailableAvailableNot AvailableNarcolepsy With Cataplexy / Narcolepsy Without Cataplexy1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral18 mg
Tablet, film coatedOral4.5 mg
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00142 mg/mLALOGPS
logP4.47ALOGPS
logP4.12ChemAxon
logS-5.3ALOGPS
pKa (Strongest Basic)9.67ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity86.81 m3·mol-1ChemAxon
Polarizability35.5 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as chlorobenzenes. These are compounds containing one or more chlorine atoms attached to a benzene moiety.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Halobenzenes
Direct Parent
Chlorobenzenes
Alternative Parents
Piperidines / Aryl chlorides / Trialkylamines / Dialkyl ethers / Azacyclic compounds / Organochlorides / Hydrocarbon derivatives
Substituents
Chlorobenzene / Aryl chloride / Aryl halide / Piperidine / Tertiary amine / Tertiary aliphatic amine / Azacycle / Ether / Dialkyl ether / Organoheterocyclic compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Inverse agonist
Curator comments
Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human histamine H3 receptor subtype.
General Function
Histamine receptor activity
Specific Function
The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive a...
Gene Name
HRH3
Uniprot ID
Q9Y5N1
Uniprot Name
Histamine H3 receptor
Molecular Weight
48670.81 Da
References
  1. 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. [PubMed:21615387]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Blocker
Curator comments
Pitolisant blocked hERG channel with an IC50 exceeding therapeutic concentrations and induced a slight QTc prolongation in dogs.
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inducer
Curator comments
Induction of CYP3A4 by pitolisant was observed in vitro.
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
Pitolisant is an inhibitor of CYP2D6 with moderate potency (IC50 = 2.6 μM).
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
Curator comments
Inhibition of CYP1A2 by pitolisant was observed in vitro.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Pitilosant FDA label [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
Curator comments
Inhibition of CYP2B6 by pitolisant was observed in vitro.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Pitolisant EMA Label [File]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Pitolisant shows greater than 50% inhibition towards OCT1 (organic cation transporters 1) at 1.33 μM, and the extrapolated IC50 of pitolisant is 0.795 μM.
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da

Drug created on October 17, 2016 15:30 / Updated on November 02, 2018 07:13