Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Copenhagen Head Injury Ciclosporin Study : A Phase IIa Safety, Pharmacokinetics, and Biomarker Study of Ciclosporin in Severe Traumatic Brain Injury Patients

Kelsen, Jesper ; Karlsson, Michael LU ; Hansson, Magnus J. LU orcid ; Yang, Zhihui ; Fischer, Walter ; Hugerth, Matilda ; Nordström, Carl Henrik LU ; Åstrand, Ramona LU ; Keep, Marcus F. and Kilbaugh, Todd , et al. (2019) In Journal of Neurotrauma 36(23). p.3253-3263
Abstract

Traumatic brain injury (TBI) contributes to almost one third of all trauma-related deaths, and those that survive often suffer from long-term physical and cognitive deficits. Ciclosporin (cyclosporine, cyclosporin A) has shown promising neuroprotective properties in pre-clinical TBI models. The Copenhagen Head Injury Ciclosporin (CHIC) study was initiated to establish the safety profile and pharmacokinetics of ciclosporin in patients with severe TBI, using a novel parenteral lipid emulsion formulation. Exploratory pharmacodynamic study measures included microdialysis in brain parenchyma and protein biomarkers of brain injury in the cerebrospinal fluid (CSF). Sixteen adult patients with severe TBI (Glasgow Coma Scale 4-8) were included,... (More)

Traumatic brain injury (TBI) contributes to almost one third of all trauma-related deaths, and those that survive often suffer from long-term physical and cognitive deficits. Ciclosporin (cyclosporine, cyclosporin A) has shown promising neuroprotective properties in pre-clinical TBI models. The Copenhagen Head Injury Ciclosporin (CHIC) study was initiated to establish the safety profile and pharmacokinetics of ciclosporin in patients with severe TBI, using a novel parenteral lipid emulsion formulation. Exploratory pharmacodynamic study measures included microdialysis in brain parenchyma and protein biomarkers of brain injury in the cerebrospinal fluid (CSF). Sixteen adult patients with severe TBI (Glasgow Coma Scale 4-8) were included, and all patients received an initial loading dose of 2.5 mg/kg followed by a continuous infusion for 5 days. The first 10 patients received an infusion dosage of 5 mg/kg/day whereas the subsequent 6 patients received 10 mg/kg/day. No mortality was registered within the study duration, and the distribution of adverse events was similar between the two treatment groups. Pharmacokinetic analysis of CSF confirmed dose-dependent brain exposure. Between- and within-patient variability in blood concentrations was limited, whereas CSF concentrations were more variable. The four biomarkers, glial fibrillary acidic protein, neurofilament light, tau, and ubiquitin carboxy-terminal hydrolase L1, showed consistent trends to decrease during the 5-day treatment period, whereas the samples taken on the days after the treatment period showed higher values in the majority of patients. In conclusion, ciclosporin, as administered in this study, is safe and well tolerated. The study confirmed that ciclosporin is able to pass the blood-brain barrier in a TBI population and provided an initial biomarker-based signal of efficacy.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biomarkers, ciclosporin, NeuroSTAT, pharmacokinetics, traumatic brain injury
in
Journal of Neurotrauma
volume
36
issue
23
pages
11 pages
publisher
Mary Ann Liebert, Inc.
external identifiers
  • scopus:85075647266
  • pmid:31210099
ISSN
0897-7151
DOI
10.1089/neu.2018.6369
language
English
LU publication?
yes
id
08bac47c-06d1-4523-aaa1-d335b1b10f41
date added to LUP
2019-12-17 08:20:54
date last changed
2024-05-15 03:56:21
@article{08bac47c-06d1-4523-aaa1-d335b1b10f41,
  abstract     = {{<p>Traumatic brain injury (TBI) contributes to almost one third of all trauma-related deaths, and those that survive often suffer from long-term physical and cognitive deficits. Ciclosporin (cyclosporine, cyclosporin A) has shown promising neuroprotective properties in pre-clinical TBI models. The Copenhagen Head Injury Ciclosporin (CHIC) study was initiated to establish the safety profile and pharmacokinetics of ciclosporin in patients with severe TBI, using a novel parenteral lipid emulsion formulation. Exploratory pharmacodynamic study measures included microdialysis in brain parenchyma and protein biomarkers of brain injury in the cerebrospinal fluid (CSF). Sixteen adult patients with severe TBI (Glasgow Coma Scale 4-8) were included, and all patients received an initial loading dose of 2.5 mg/kg followed by a continuous infusion for 5 days. The first 10 patients received an infusion dosage of 5 mg/kg/day whereas the subsequent 6 patients received 10 mg/kg/day. No mortality was registered within the study duration, and the distribution of adverse events was similar between the two treatment groups. Pharmacokinetic analysis of CSF confirmed dose-dependent brain exposure. Between- and within-patient variability in blood concentrations was limited, whereas CSF concentrations were more variable. The four biomarkers, glial fibrillary acidic protein, neurofilament light, tau, and ubiquitin carboxy-terminal hydrolase L1, showed consistent trends to decrease during the 5-day treatment period, whereas the samples taken on the days after the treatment period showed higher values in the majority of patients. In conclusion, ciclosporin, as administered in this study, is safe and well tolerated. The study confirmed that ciclosporin is able to pass the blood-brain barrier in a TBI population and provided an initial biomarker-based signal of efficacy.</p>}},
  author       = {{Kelsen, Jesper and Karlsson, Michael and Hansson, Magnus J. and Yang, Zhihui and Fischer, Walter and Hugerth, Matilda and Nordström, Carl Henrik and Åstrand, Ramona and Keep, Marcus F. and Kilbaugh, Todd and Wang, Kevin K.W. and Møller, Kirsten and Juhler, Marianne and Elmér, Eskil}},
  issn         = {{0897-7151}},
  keywords     = {{biomarkers; ciclosporin; NeuroSTAT; pharmacokinetics; traumatic brain injury}},
  language     = {{eng}},
  number       = {{23}},
  pages        = {{3253--3263}},
  publisher    = {{Mary Ann Liebert, Inc.}},
  series       = {{Journal of Neurotrauma}},
  title        = {{Copenhagen Head Injury Ciclosporin Study : A Phase IIa Safety, Pharmacokinetics, and Biomarker Study of Ciclosporin in Severe Traumatic Brain Injury Patients}},
  url          = {{http://dx.doi.org/10.1089/neu.2018.6369}},
  doi          = {{10.1089/neu.2018.6369}},
  volume       = {{36}},
  year         = {{2019}},
}