Pitolisant
Pitolisant Uses, Dosage, Side Effects, Food Interaction and all others data.
Pitolisant is a selective antagonist or inverse agonist of the histamine H3 receptor used to treat type 1 or 2 narcolepsy. 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. About 60-70% of patients with narcolepsy experience cataplexy, which is a sudden loss of muscle tone triggered by positive or negative emotions. 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. The therapeutic effectiveness of pitolisant was comparable to that of modafinil. 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. Adolescent patients with cataplexy also experienced a slight improvement in the frequency and severity of symptoms ; 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 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.
Pitolisant promotes wakefulness in narcolepsy by enhancing histaminergic signalling in the central nervous system. It does not significantly bind to H1, H2, or H4 receptors. 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)). Pitolisant also improved the frequency and severity of narcolepsy-associated cataplexy. Pitolisant acts as a blocker at hERG channels. In two 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).
| Trade Name | Pitolisant |
| Availability | Prescription only |
| Generic | Pitolisant |
| Pitolisant Other Names | Pitolisant |
| Related Drugs | Xyrem, Wakix, Xywav, Adderall, methylphenidate, Concerta, modafinil, Ritalin, dextroamphetamine |
| Weight | 17.8mg, 4.45mg |
| Type | Oral tablet |
| Formula | C17H26ClNO |
| Weight | Average: 295.85 Monoisotopic: 295.1702922 |
| Protein binding | The serum protein binding of pitolisant is approximately 91% to 96%. Pitolisant is mainly bound to serum albumin and alpha-1 glycoprotein. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Pitolisant is an antagonist and inverse agonist at the histamine H3 receptor that is used to treat narcolepsy in adults.
Pitolisant is indicated for the treatment of narcolepsy with or without cataplexy and excessive daytime sleepiness in narcolepsy in adult patients.
Pitolisant is also used to associated treatment for these conditions: Excessive Daytime Sleepiness, Narcolepsy With Cataplexy, Narcolepsy Without Cataplexy
How Pitolisant works
Signalling of histaminergic neurons plays a key role in activating the arousal system with widespread projections to the whole brain via activating orexin receptors. Narcolepsy is characterized by insufficient neurotransmission by orexins, or hypocretins, which are excitatory peptides released by neurons located from the lateral hypothalamus. These neurons project to aminergic neurons, such as histaminergic or noradrenergic neurons, that are responsible for the effects of orexin and control of wakefulness. Histamine H3 receptors are presynaptic inhibitory autoreceptors that are located in the cerebral cortex, hypothalamus, hippocampus, and basal ganglia. H3 receptors promote the re-uptake of histamine at synaptic terminals and attenuate further histamine release into the synapse. By blocking H3 autoreceptors and increasing the levels of histamine transmitters at the synapse, pitolisant enhances the activity of histaminergic neurons and promotes wakefulness. Inverse agonism of pitolisant at H3 receptors also leads to enhanced synthesis and release of endogenous histamine over the basal level.
Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human H3 receptor and mediates its pharmacological action at the presynaptic level. It is thought to bind to the antagonist binding site of the H3 receptor, which is located within the transmembrane core just below the extracellular loops. Piperidines form a salt bridge with Glu206 in the membrane-spanning segment, and the hydroxyl of Tyr374 is H-bonded with the central oxygen of piperidine. 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 the nucleus accumbens. At lower nanomolar concentrations, pitolisant acts as an inverse agonist at H3 receptors and enhances the release of endogenous histamine over the basal level.
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.
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. 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.
Food Interaction
- 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.
- Take with or without food. A high-fat meal had no clinically significant effects on drug pharmacokinetics.
Pitolisant Drug Interaction
Major: hydroxychloroquine, fluoxetineModerate: loratadine, emtricitabine / tenofovir alafenamide, acetaminophen, cetirizineUnknown: 5-hydroxytryptophan, amphetamine / dextroamphetamine, fluticasone nasal, levocarnitine, pregabalin, metoprolol, amlodipine, armodafinil, bioflavonoids, beclomethasone, solriamfetol, cyanocobalamin, cholecalciferol, sodium oxybate
Pitolisant Disease Interaction
Major: hepatic impairmentModerate: bipolar disorders, psychotic disorders, arrhythmias, renal disease
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. Pitolisant is thought to be equally distributed between red blood cells and plasma. 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.
Elimination Route
Pitolisant is rapidly and well absorbed following oral administration, resulting in the drug being 90% absorbed. In healthy individuals receiving an oral dose of 20 mg, the Cmax was approximately 30 ng/mL. 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. The Tmax was typically reached approximately 3 hours following administration. 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. The absolute bioavailability of pitolisant has not been determined.
Half Life
Pitolisant has a plasma half-life of 10-12 hours. After administration of a single dose of 35.6 mg, the median half-life of pitolisant was approximately 20 hours.
Clearance
The apparent oral clearance (CL/F) of pitolisant was 43.9 L/hr following a single dose of 35.6 mg. The clearance rate is expected to be lower with increasing age.
Elimination Route
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. About 25% of the total dose administered is excreted through expired air as metabolites, and a small fraction (8
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