Piperidine, 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-

Absorption

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.

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.

The Uses of Piperidine, 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-

Pitolisant is a potent and selective nonimidazole inverse agonist at the recombinant human histamine H3 receptor. Pitolisant is also used in the treatment of patients with narcolepsy, excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep, hypnagogic hallucinations and sleep paralysis

Indications

Pitolisant is indicated for the treatment of narcolepsy with or without cataplexy and excessive daytime sleepiness in narcolepsy in adult patients.

Background

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.

Definition

ChEBI: Pitolisant is an organochlorine compound.

Pharmacokinetics

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).

Metabolism

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). 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. 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.
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.