Abstract Details

Title Hormonal Contraceptive and Pitolisant CYP3A4 Induction

Topic Sleep

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 7-035

Objective To assess the inducer potential of pitolisant on cytochrome CYP3A4 responsible for oral hormonal anticonceptive drug metabolism.

Background Psychostimulants (eg, modafinil) are contraindicated in narcoleptic patients taking oral contraceptives as they reduce plasma levels of the contraceptives by inducing CYP3A4 activity. Pitolisant is a novel wake-promoting and anticataplectic agent approved in Europe for the treatment of narcolepsy. We assessed its CYP3A4-inducing potential in vitro and in vivo to possibly offer a therapeutic alternative for patients with narcolepsy wishing to continue their hormonal anticonceptive treatment.

Design/Methods In cultured human hepatocytes, pitolisant inducing potential was evaluated on CYP3A4 mRNA and enzyme catalytic activity. In vivo induction was evaluated in volunteers receiving pitolisant once daily at 36 mg for 7 to 28 days with two approaches. In the traditional approach, the metabolism of midazolam was evaluated. In the second and more recent approach (Goodenough AK, et al. Chem Res Toxicol. 2011;24(9):1575-1585), formation of a characteristic cholesterol metabolite (4-β-hydroxycholesterol [4βHC]) was measured using a novel LC/MS method requiring only 50 μL serum samples.

Results Pitolisant demonstrated only minor changes in CYP3A4 mRNA levels, whereas CYP3A4 catalytic activity was not induced in hepatocytes across 6 subjects. In 18 volunteers receiving 36 mg pitolisant once daily for 8 days, minor midazolam exposure modifications were evidenced without change in metabolite formation via CYP3A4. In another group of 48 volunteers receiving 18 to 45 mg pitolisant once daily for up to 28 days, 4βHC levels were not modified. This new test was validated in 18 other volunteers receiving for 8 days 600 mg/day of rifampicin, a prototypic CYP3A4-inducer, in which 4βHC levels were increased (P<0.00001).

Conclusions Pitolisant, at therapeutic dose, is devoid of any inducer activity on CYP3A4 and, therefore, represents a valuable alternative for treating excessive daytime sleepiness and cataplexy in female patients with narcolepsy taking hormonal contraceptive drugs.

Authors/Disclosures
Philippe Robert, MD (Hopital Cimiez) PRESENTER	No disclosure on file
	No disclosure on file

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