Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy

Beatrice Setnik, Michael McDonnell, Catherine Mills, Catherine Scart-Grès, Philippe Robert, Jeffrey M Dayno, Jean-Charles Schwartz, Beatrice Setnik, Michael McDonnell, Catherine Mills, Catherine Scart-Grès, Philippe Robert, Jeffrey M Dayno, Jean-Charles Schwartz

Abstract

Objectives: To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy.

Methods: Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking ("at this moment") visual analog scale.

Results: In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration.

Conclusions: In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant.

Clinical trial registration: ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://ichgcp.net/clinical-trials-registry/NCT03152123.

Keywords: drug abuse; narcolepsy; pitolisant.

© Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].

Figures

Figure 1.
Figure 1.
Study design and participant disposition. HCl = hydrochloride.
Figure 2.
Figure 2.
Primary pharmacodynamic measure, Drug Liking VAS, over time (completers population, N = 38). Error bars represent ±1 SE. SE = standard error; VAS = visual analog scale.
Figure 3.
Figure 3.
Key secondary pharmacodynamic measures over time (completers population, N = 38) for (A) Overall Drug Liking, (B) Take Drug Again, (C) Good Drug Effects, and (D) High VAS. Error bars represent ±1 SE. SE = standard error; VAS = visual analog scale.
Figure 4.
Figure 4.
Serum concentration of pitolisant over time (pharmacokinetic population, N = 40). SD = standard deviation.

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