Safety and Tolerability of Cyclosporin A in Severe Traumatic Brain Injury Patients: Results from a Prospective Randomized Trial

Abstract

Cyclosporin A (CsA) has recently been proposed for use in the early phase after traumatic brain injury (TBI), for its ability to preserve mitochondrial integrity in experimental brain injury models, and thereby provide improved behavioral outcomes as well as significant histological protection. The aim of this prospective, randomized, double-blind, dual-center, placebo-controlled trial was to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of CsA in patients with severe TBI. Fifty adult severe TBI patients were enrolled over a 22-month period. Within 12 h of the injury patients received 5 mg=kg of CsA infused over 24 h, or placebo. Blood urea nitrogen (BUN), creatinine, hemoglobin, platelets, white blood cell count (WBC), and a hepatic panel were monitored on admission, and at 12, 24, 36, and 48 h, and on days 4 and 7. Potential adverse events (AEs) were also recorded. Neurological outcome was recorded at 3 and 6 months after injury. This study revealed only transient differences in BUN levels at 24 and 48 h and for WBC counts at 24 h between the CsA and placebo patients. These modest differences were not clinically significant in that they did not negatively impact on patient course. Both BUN and creatinine values, markers of renal function, remained within their normal limits over the entire monitoring period. There were no significant differences in other mean laboratory values, or in the incidence of AEs at any other measured time point. Also, no significant difference was demonstrated for neurological outcome. Based on these results, we report a good safety profile of CsA infusion when given at the chosen dose of 5 mg=kg, infused over 24 h, during the early phase after severe head injury in humans, with the aim of neuroprotection.

Cellular Alterations in Human Traumatic Brain Injury: Changes in Mitochondrial Morphology Reflect Regional Levels of Injury Severity

“…2,[57][58][59][60] It has now been demonstrated that inhibition of the MPT after TBI is a viable neuroprotective approach [61][62][63] and can improve the favorable outcomes of severe TBI patients. 64,65 The several interrelated mitochondrial dynamic processes, such as fusion, fission, anterograde and retrograde transport in axons, turnover, and interaction with cytoskeleton and other organelles, form a complex interacting network that governs mitochondrial function and thereby cellular integrity. 4 Pharmacologic approaches toward minimizing abnormal alterations in mitochondrial dynamics warrant exploration and might exert neuroprotection beyond what has been observed with inhibitors of the mitochondrial permeability transition that help maintain mitochondrial and cellular integrity.…”

Exposure of Cyclosporin A in Whole Blood, Cerebral Spinal Fluid, and Brain Extracellular Fluid Dialysate in Adults with Traumatic Brain Injury

“…2 Published literature to date does not reveal a significant increase in adverse events or laboratory abnormalities associated with the use of CsA compared with placebo, despite its historically narrow therapeutic index. 2,11 The previously published safety analysis from this trial demonstrated that patients treated with CsA had a mean creatinine and BUN within normal limits, and no statistically significant difference was noted in liver function tests, hemoglobin, or platelets compared to placebo. 11 The safety profile of CsA may be improved by PK studies that allow for precise determination of dosing strategies to achieve optimal therapeutic serum concentrations for neuroprotection in TBI patients.…”

“…The safety and tolerability of this CsA dosing regimen have been reported previously, as part of the same trial. 11 CsA concentrations were determined in whole blood, CSF, and ECF, obtained via microdialysis. Whole blood, CSF, and ECF dialysate samples were drawn at 1 h before CsA administration, and thereafter at 75 min, 4 h, 6 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 72 h after administration.…”

“…In the absence of CsA, activation of the mitochondrial permeability transition pore is associated with uncoupling of oxidative phosphorylation, osmotic swelling, and lysing of the mitochondrial membrane. 3,[8][9][10][11][12] CsA has demonstrated efficacy and safety in in vivo animal and preliminary human studiesof TBI 2,4,7,11,13 However, no studies todate have reported the exposure of CsA in multiple biofluids following neurotrauma. The aim of the current study is to describe the pharmacokinetic (PK) parameters of CsA in adults with TBI by sampling drug concentrationsinthewholeblood,cerebrospinalfluid (CSF), and brain extracellular fluid (ECF) dialysate.…”

Commentary and Update on “The Mitochondrial Permeability Transition Pore Provides a Key to the Diagnosis and Treatment of Traumatic Brain Injury”

“…A further substantiation of the role which opening of the MPTP plays in the origin of TBI is the observation that the antibiotic cyclosporine had some success in treating TBI [12][13][14][15]. Cyclosporine acts quite specifically in binding to the mitochondrial protein cyclophilin which forms a part of the MPTP [16].…”