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.

Use of Neuroprotective agents for Traumatic Brain Injury

“…However there is no significant effect of its use in 6-month favorable outcomes or mortality rates. Also cohort study groups of Hatton et al and other drug concentration studies confirm that best blood and cerebrospinal fluid (CSF) CysA depositions resulted from its high doses and fortunately the wide therapeutic window [28,[59][60][61]. Both of the included studies have a 5 mg/kg intervention on their design protocols, also Hatton et al recommended a 2.5 mg/kg bolus dose in 2 hours of TBI insult following by 5 mg/kg/day for 72 hours, as optimal dosing strategy for further clinical trials study design.…”

“…There was no trial for NeuroAid use in TBI. were [28,59,60]. The other two papers' population been analyzed at all were 89 patients [29,61].…”

Mind the Gaps: Ontogeny of Human Brain P-gp and Its Impact on Drug Toxicity

“…Cyclosporin A (CsA) is a potent, amino acid-containing immunosuppressant. It is a P-gp substrate (89) that usually shows restricted distribution to the brain (90). However, severe neurotoxicity is a recognized complication of CsA that can manifest as seizures, acute encephalopathy, coma, cerebral hemorrhage, and cortical blindness.…”

Multi-Center Pre-clinical Consortia to Enhance Translation of Therapies and Biomarkers for Traumatic Brain Injury: Operation Brain Trauma Therapy and Beyond

“…For example, in studies targeting the pre-clinical development of therapies for pediatric TBI, Kilbaugh et al ( 44 ) used rodent and piglet models concurrently focusing on a single therapy (cyclosporin A), studying a range of doses, and selecting effects on mitochondria as the target mechanism. Cyclosporin A, in OBTT showed considerable model dependence in effects, ranging from modest benefit in the FPI model, no benefit in CCI, and toxicity in PBBI ( 13 )–suggesting that dose, timing, and duration of treatment could be very challenging to optimize in human TBI, unless a specific TBI phenotype and injury severity level were targeted ( 65 ). Cyclosporin A indeed has considerable toxicity with use in humans ( 66 ).…”