Pitolisant-supported bridging during drug holidays to deal with tolerance to modafinil in patients with narcolepsy.

Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil. Narcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to "bridge" the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients' diaries. 41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly. Patients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil. Clinical Trials.gov Identifier NCT05321355.

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Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YW reports honoraria for educational presentations and consultations from Angelini Pharma, Arvelle Therapeutics, Bayer AG, BIAL, Bioprojet, Bristol-Myers Squibb, JAZZ pharmaceuticals, Eisai, LivaNova, Novartis, Precisis and UCB Pharma. SG received compensation for professional services from Abbott, Abbvie, Bial, Medtronic, UCB and Zambon; research grants from Abbott, Boston Scientific, MagVenture, German Research Council and German Ministry of Education and Health. UK received honoraria for consulting from AOP Health, Bioprojet Pharma, Jazz Pharmaceuticals and Takeda Pharma. CL received honoraria for consulting and educational presentations from Bioprojet, UCB and Jazz Pharmaceuticals. Financial disclosure of VF, DA and EE: none. Non-financial disclosure of YW, SG, UK, CL, VF, DA and EE: none.