PMID- 34961705
OWN - NLM
STAT- MEDLINE
DCOM- 20220602
LR  - 20220705
IS  - 1873-5010 (Electronic)
IS  - 1569-1993 (Linking)
VI  - 21
IP  - 3
DP  - 2022 May
TI  - Safety and pharmacokinetics of Roscovitine (Seliciclib) in cystic fibrosis 
      patients chronically infected with Pseudomonas aeruginosa, a randomized, 
      placebo-controlled study.
PG  - 529-536
LID - S1569-1993(21)02167-6 [pii]
LID - 10.1016/j.jcf.2021.10.013 [doi]
AB  - 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.
CI  - Copyright (c) 2021. Published by Elsevier B.V.
FAU - Meijer, Laurent
AU  - Meijer L
AD  - ManRos Therapeutics, Presqu'ile de Perharidy, Roscoff 29680, France. Electronic 
      address: meijer@manros-therapeutics.com.
FAU - Hery-Arnaud, Genevieve
AU  - Hery-Arnaud G
AD  - Unite de Bacteriologie, Hopital de la Cavale Blanche, CHRU Brest, Brest cedex 
      29609, France; Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest 29200, France.
FAU - Leven, Cyril
AU  - Leven C
AD  - Departement de Biochimie et Pharmaco-Toxicologie, CHRU Brest, Brest cedex 29609, 
      France; Univ Brest, EA 3878, GETBO, Brest 29200, France.
FAU - Nowak, Emmanuel
AU  - Nowak E
AD  - INSERM CIC 1412, Brest University Hospital, Brest cedex 29609, France.
FAU - Hillion, Sophie
AU  - Hillion S
AD  - Laboratoire d'Immunologie et Immunotherapie, CHRU de Brest, INSERM U1227, 2 
      avenue Foch, BP824, 29609 Brest cedex, France.
FAU - Renaudineau, Yves
AU  - Renaudineau Y
AD  - Laboratoire d'Immunologie et Immunotherapie, CHRU de Brest, INSERM U1227, 2 
      avenue Foch, BP824, 29609 Brest cedex, France.
FAU - Durieu, Isabelle
AU  - Durieu I
AD  - 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-Benite 69495, 
      France.
FAU - Chiron, Raphael
AU  - Chiron R
AD  - CHU Montpellier, Maladies Respiratoires, Hopital Arnaud de Villeneuve, 371, 
      avenue du Doyen Gaston Giraud, Montpellier 34295, France.
FAU - Prevotat, Anne
AU  - Prevotat A
AD  - Service de pneumologie, CHR - Hopital Calmette, Boulevard du Pr. Leclercq, Lille 
      59037, France.
FAU - Fajac, Isabelle
AU  - Fajac I
AD  - APHP.Centre - Universite de Paris, 27 rue du Faubourg Saint-Jacques, Paris 75014, 
      France.
FAU - Hubert, Dominique
AU  - Hubert D
AD  - APHP.Centre - Universite de Paris, 27 rue du Faubourg Saint-Jacques, Paris 75014, 
      France.
FAU - Murris-Espin, Marlene
AU  - Murris-Espin M
AD  - CHU Toulouse, CRCM adulte, Service de Pneumologie, Clinique des Voies 
      Respiratoires. Hopital Larrey, 24 chemin de Pouvourville, Toulouse 31059, France.
FAU - Huge, Sandrine
AU  - Huge S
AD  - Centre Hospitalier Bretagne Atlantique, CRCM Mixte 56, 20 Boulevard du general 
      Maurice Guillaudot, Vannes cedex 56017, France.
FAU - Danner-Boucher, Isabelle
AU  - Danner-Boucher I
AD  - CHU de Nantes, Service de Pneumologie, Hopital Nord Laennec, Boulevard 
      Jacques-Monod, Nantes 44093, Saint-Herblain, France.
FAU - Ravoninjatovo, Bruno
AU  - Ravoninjatovo B
AD  - Centre de Ressources et de Competences de la Mucoviscidose, Maladies 
      Respiratoires et Allergiques, Hopital Maison Blanche - CHU Reims, 45 rue 
      Cognacq-Jay, 51100 Reims, France.
FAU - Leroy, Sylvie
AU  - Leroy S
AD  - CHU de Nice, Hopital Pasteur, Service de Pneumologie, Oncologie Thoracique et 
      Soins Intensifs Respiratoires, 30 Voie Romaine, CS 51069, Nice cedex 1 06001, 
      France.
FAU - Macey, Julie
AU  - Macey J
AD  - CHU Bordeaux, Hopital Haut-Leveque, Service de Pneumologie, Avenue de Magellan, 
      Pessac cedex 33604, France.
FAU - Urban, Thierry
AU  - Urban T
AD  - Departement de Pneumologie, CHU Angers, Site de Larrey, 4 rue de Larrey, Angers 
      cedex 49933, France.
FAU - Rault, Gilles
AU  - Rault G
AD  - Fondation Ildys, Centre de Perharidy, Roscoff cedex 29684, France.
FAU - Mottier, Dominique
AU  - Mottier D
AD  - Departement de Biochimie et Pharmaco-Toxicologie, CHRU Brest, Brest cedex 29609, 
      France.
FAU - Berre, Rozenn Le
AU  - Berre RL
AD  - Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest 29200, France; Departement de 
      Medecine Interne et Pneumologie, CHRU Brest, Brest cedex 29609, France.
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20211224
PL  - Netherlands
TA  - J Cyst Fibros
JT  - Journal of cystic fibrosis : official journal of the European Cystic Fibrosis 
      Society
JID - 101128966
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0ES1C2KQ94 (Roscovitine)
SB  - IM
MH  - Animals
MH  - *Cystic Fibrosis/diagnosis/drug therapy/metabolism/microbiology
MH  - Double-Blind Method
MH  - Humans
MH  - Protein Kinase Inhibitors/therapeutic use
MH  - Pseudomonas Infections/drug therapy/metabolism
MH  - Pseudomonas aeruginosa
MH  - Quality of Life
MH  - *Roscovitine/therapeutic use
OTO - NOTNLM
OT  - Clinical trial
OT  - Cystic fibrosis
OT  - Inflammation
OT  - Pseudomonas aeruginosa
OT  - Roscovitine
OT  - Seliciclib
EDAT- 2021/12/29 06:00
MHDA- 2022/06/03 06:00
CRDT- 2021/12/28 05:49
PHST- 2021/07/14 00:00 [received]
PHST- 2021/10/17 00:00 [revised]
PHST- 2021/10/19 00:00 [accepted]
PHST- 2021/12/29 06:00 [pubmed]
PHST- 2022/06/03 06:00 [medline]
PHST- 2021/12/28 05:49 [entrez]
AID - S1569-1993(21)02167-6 [pii]
AID - 10.1016/j.jcf.2021.10.013 [doi]
PST - ppublish
SO  - J Cyst Fibros. 2022 May;21(3):529-536. doi: 10.1016/j.jcf.2021.10.013. Epub 2021 
      Dec 24.