Description: Head injury is a complex disease where the primary injury initiates a chemical cascade of central mediator release leading to secondary insults within the central nervous system and systemically. Morbidity and mortality rates remain high despite advances in guidelines for clinical management. Several potential mechanisms of secondary injury have been identified and therapeutic strategies for intervention have been tested in animal and human trials. Despite preliminary evidence of efficacy in small clinical trials, no drug has shown significant benefit when tested in larger well designed randomized investigations. Lack of pharmacokinetic data to guide dosing for specific pharmacodynamic endpoints is one of several possible reasons for failure of investigational drugs to demonstrate benefit. Recent evidence from animal research suggests a protective effect of Cyclosporin A (CsA) in neural trauma. CsA given to mice and rats following severe cortical contusion reduced neuronal injury by approximately 50%. CsA is a difficult drug to model and predict response. Our preliminary data from two TBI patients demonstrates a marked variability in serum trough concentrations of CsA. The systemic effects of head injury and the requirement for adequate delivery of drug to the injured brain mandate preliminary dose finding studies prior to progressing into clinical trials. In this pilot clinical trial, we will systematically define CsA pharmacokinetic and pharmacodynamic endpoints in a homogenous population of patients with traumatic brain injury. We will measure serum and cerebrospinal fluid (CSF) concentrations of drug and surrogate biochemical markers of secondary injury to identify potential pharmacodynamic endpoints useful in designing optimal drug dosing strategies. This dose-finding proposal will characterize the pharmacokinetic profile of CsA and provide preliminary safety data in patients with TBI. Information from this pilot study will be used to establish a dosing strategy for a future Phase 11 prospective randomized trial. We will test the hypothesis that clinically approved doses of CsA can be safely administered to patients with TBI and achieve measurable concentrations in the CSF and serum.