Safety and pharmacokinetics of Roscovitine (Seliciclib) in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa, a randomized, placebo-controlled study.

Autor: Meijer L; ManRos Therapeutics, Presqu'île de Perharidy, Roscoff 29680, France. Electronic address: meijer@manros-therapeutics.com., Hery-Arnaud G; Unité de Bactériologie, Hôpital de la Cavale Blanche, CHRU Brest, Brest cedex 29609, France; Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest 29200, France., Leven C; Département de Biochimie et Pharmaco-Toxicologie, CHRU Brest, Brest cedex 29609, France; Univ Brest, EA 3878, GETBO, Brest 29200, France., Nowak E; INSERM CIC 1412, Brest University Hospital, Brest cedex 29609, France., Hillion S; Laboratoire d'Immunologie et Immunothérapie, CHRU de Brest, INSERM U1227, 2 avenue Foch, BP824, 29609 Brest cedex, France., Renaudineau Y; Laboratoire d'Immunologie et Immunothérapie, CHRU de Brest, INSERM U1227, 2 avenue Foch, BP824, 29609 Brest cedex, France., Durieu I; Research on Healthcare Performance (RESHAPE), INSERM U1290, Claude Bernard Lyon 1 University, 8 Avenue Rockefeller, 69003 Lyon, France; Department of Internal Medicine, Cystic Fibrosis Center, Hospices Civils de Lyon, Pierre-Bénite 69495, France., Chiron R; CHU Montpellier, Maladies Respiratoires, Hôpital Arnaud de Villeneuve, 371, avenue du Doyen Gaston Giraud, Montpellier 34295, France., Prevotat A; Service de pneumologie, CHR - Hôpital Calmette, Boulevard du Pr. Leclercq, Lille 59037, France., Fajac I; APHP.Centre - Université de Paris, 27 rue du Faubourg Saint-Jacques, Paris 75014, France., Hubert D; APHP.Centre - Université de Paris, 27 rue du Faubourg Saint-Jacques, Paris 75014, France., Murris-Espin M; CHU Toulouse, CRCM adulte, Service de Pneumologie, Clinique des Voies Respiratoires. Hôpital Larrey, 24 chemin de Pouvourville, Toulouse 31059, France., Huge S; Centre Hospitalier Bretagne Atlantique, CRCM Mixte 56, 20 Boulevard du général Maurice Guillaudot, Vannes cedex 56017, France., Danner-Boucher I; CHU de Nantes, Service de Pneumologie, Hôpital Nord Laennec, Boulevard Jacques-Monod, Nantes 44093, Saint-Herblain, France., Ravoninjatovo B; Centre de Ressources et de Compétences de la Mucoviscidose, Maladies Respiratoires et Allergiques, Hôpital Maison Blanche - CHU Reims, 45 rue Cognacq-Jay, 51100 Reims, France., Leroy S; CHU de Nice, Hôpital Pasteur, Service de Pneumologie, Oncologie Thoracique et Soins Intensifs Respiratoires, 30 Voie Romaine, CS 51069, Nice cedex 1 06001, France., Macey J; CHU Bordeaux, Hôpital Haut-Lévêque, Service de Pneumologie, Avenue de Magellan, Pessac cedex 33604, France., Urban T; Département de Pneumologie, CHU Angers, Site de Larrey, 4 rue de Larrey, Angers cedex 49933, France., Rault G; Fondation Ildys, Centre de Perharidy, Roscoff cedex 29684, France., Mottier D; Département de Biochimie et Pharmaco-Toxicologie, CHRU Brest, Brest cedex 29609, France., Berre RL; Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest 29200, France; Département de Médecine Interne et Pneumologie, CHRU Brest, Brest cedex 29609, France.
Jazyk: angličtina
Zdroj: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society [J Cyst Fibros] 2022 May; Vol. 21 (3), pp. 529-536. Date of Electronic Publication: 2021 Dec 24.
DOI: 10.1016/j.jcf.2021.10.013
Abstrakt: Background: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects.
Methods: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks).
Results: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group.
Conclusion: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.
(Copyright © 2021. Published by Elsevier B.V.)
Databáze: MEDLINE
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