title: Exposure of cyclosporin A in whole blood, cerebral spinal fluid, and brain extracellular fluid dialysate in adults with traumatic brain injury.
abstract: Cyclosporin A (CsA), an immunosuppressive medication traditionally used in the prevention of post-transplant rejection, is a promising neuroprotective agent for traumatic brain injury (TBI). Preliminary studies in animals and humans describe the efficacy and safety of CsA when administered following neurotrauma. The objective of this study is to describe CsA exposure in adults with severe TBI by assessing concentrations in whole blood, cerebrospinal fluid (CSF), and brain extracellular fluid (ECF) dialysate as measured by brain microdialysis. Severe TBI patients were enrolled in a randomized controlled trial following the written informed consent of their legal guardians. Patients received either CsA 5 mg/kg as a continuous infusion over 24 h, or matching placebo. Noncompartmental exposure analyses were performed using CsA concentrations in whole blood, CSF, and ECF dialysate. There were 37 patients randomized to the CsA arm of the trial and included in this exposure analysis. CsA was detected in the ECF dialysate and CSF at a fraction of the whole blood concentration. Mean CsA maximum concentrations were achieved at 24 and 30 h from the start of the 24 h infusion, in the CSF and ECF dialysate, respectively. A correlation was found between ECF dialysate and CSF concentrations. CsA was detected in the blood, CSF, and brain ECF dialysate. CsA exposure characteristic differences exist for whole blood, CSF, and ECF dialysate in severe TBI patients when administered as a continuous intravenous infusion. These exposure characteristics should be used for safer CsA dose optimization to achieve target CsA concentrations for neuroprotection in future TBI studies.
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Medical College of Virginia Campus, Richmond, Virginia 23298-0533, USA. gbrophy@vcu.edu
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Brophy
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Mazzeo
authors.forename: Satjit
authors.initials: S
authors.lastname: Brar
authors.forename: Oscar Luis
authors.initials: OL
authors.lastname: Alves
authors.forename: Kristen
authors.initials: K
authors.lastname: Bunnell
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gilman
authors.forename: Tom
authors.initials: T
authors.lastname: Karnes
authors.forename: Ron L
authors.initials: RL
authors.lastname: Hayes
authors.forename: Ross
authors.initials: R
authors.lastname: Bullock
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood* / Q000134:cerebrospinal fluid*; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D017551:Microdialysis / Q000379:methods; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid; D011446:Prospective Studies; D014696:Ventriculostomy / Q000379:methods; D055815:Young Adult
chemical_list: D018696:Neuroprotective Agents; D016572:Cyclosporine
references.citation: Ther Drug Monit. 2004 Oct;26(5):524-8
references.pmid: 15385835
references.citation: J Neurosurg. 1996 Sep;85(3):476-81
references.pmid: 8751635
references.citation: Brain Res. 1992 Nov 6;595(1):145-8
references.pmid: 1467951
references.citation: J Neurotrauma. 2003 Dec;20(12):1339-50
references.pmid: 14748982
references.citation: Brain. 2012 Apr;135(Pt 4):1268-80
references.pmid: 22116192
references.citation: MMWR Surveill Summ. 2011 May 6;60(5):1-32
references.pmid: 21544045
references.citation: Transplantation. 1989 May;47(5):806-10
references.pmid: 2655218
references.citation: J Neurotrauma. 1999 Sep;16(9):783-92
references.pmid: 10521138
references.citation: J Neurotrauma. 2006 Jan;23(1):109-16
references.pmid: 16430377
references.citation: J Neurotrauma. 2002 Jul;19(7):829-41
references.pmid: 12184853
references.citation: J Clin Pharmacol. 1987 Mar;27(3):243-8
references.pmid: 3680581
references.citation: Clin Pharmacokinet. 2010 Mar;49(3):141-75
references.pmid: 20170205
references.citation: Trends Neurosci. 1998 Mar;21(3):95-7
references.pmid: 9530913
references.citation: J Neurotrauma. 2009 Dec;26(12):2195-206
references.pmid: 19621985
references.citation: J Neurochem. 1992 Mar;58(3):931-40
references.pmid: 1738000
references.citation: J Cereb Blood Flow Metab. 2011 Feb;31(2):658-70
references.pmid: 20717122
references.citation: N Engl J Med. 2008 Jul 31;359(5):473-81
references.pmid: 18669426
references.citation: J Neurotrauma. 1999 Jun;16(6):511-21
references.pmid: 10391367
references.citation: Neuroreport. 2003 Mar 3;14(3):463-6
references.pmid: 12634504
references.citation: Am J Physiol. 1990 May;258(5 Pt 1):C755-86
references.pmid: 2185657
references.citation: Cell Calcium. 2004 Sep-Oct;36(3-4):257-64
references.pmid: 15261481
references.citation: Biochemistry. 1995 Dec 19;34(50):16440-9
references.pmid: 8845372
references.citation: Anal Bioanal Chem. 2012 Feb;402(6):2057-67
references.pmid: 22159469
references.citation: J Neurotrauma. 2004 Sep;21(9):1113-22
references.pmid: 15453982
references.citation: Neuroscience. 2000;101(2):289-95
references.pmid: 11074152
references.citation: Clin Pharmacol Ther. 1991 Nov;50(5 Pt 1):487-97
references.pmid: 1934861
references.citation: Exp Neurol. 2000 Feb;161(2):631-7
references.pmid: 10686082
references.citation: Brain Res. 1995 Dec 8;702(1-2):261-5
references.pmid: 8846086
references.citation: Transplantation. 1986 Apr;41(4):459-64
references.pmid: 3515645
references.citation: J Neurotrauma. 2011 Feb;28(2):311-8
references.pmid: 21142667
references.citation: J Neurotrauma. 2011 May;28(5):763-74
references.pmid: 21250918
references.citation: Exp Neurol. 1999 Nov;160(1):226-34
references.pmid: 10630207
references.citation: J Neurochem. 1999 Jun;72(6):2488-97
references.pmid: 10349859
references.citation: J Neurosurg. 2008 Oct;109(4):699-707
references.pmid: 18826358
references.citation: J Clin Pharmacol. 1990 Jul;30(7):643-53
references.pmid: 2391396
references.citation: J Neurosurg. 2000 Jul;93(1):37-43
references.pmid: 10883903
references.citation: Clin Pharmacol Ther. 1985 Sep;38(3):296-300
references.pmid: 3896612
references.citation: J Neurotrauma. 2005 Jan;22(1):3-41
references.pmid: 15665601