title: Cyclosporin A disposition following acute traumatic brain injury.
abstract: Although the precise mechanism of action remains to be defined, Cyclosporin A (CsA) has demonstrated potential for neuroprotection in animal models. Predictive dosing strategies for CsA in acute traumatic brain injured (TBI) patients must account for the influence of the acute phase response on drug disposition. To characterize CsA pharmacokinetic parameters early following acute TBI, serial blood samples from patients enrolled into a Phase II dose-escalation trial were analyzed. Within eight hours of injury, thirty patients admitted with acute severe TBI were prospectively randomized into three cohorts (n = 8 CsA; n = 2 placebo per cohort) in this dose-escalation trial. Patients received one of three doses (I = 0.625 mg/kg/dose; II = 1.25 mg/kg/dose; III = 2.5 mg/kg/dose) or placebo intravenously every 12 h for 72 h. Serial blood collection began prior to dose 1 and continued for 72 h following the completion of six doses. Whole blood concentrations were determined by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Pharmacokinetic parameters were determined for each patient by fitting the concentration-time profile to a two-compartmental model with first order elimination. Mean area under the curve and predicted maximal blood concentration increased with each dosing cohort (I = 9840 h*microg/L, 398 microg/L; II = 18300 h*microg/L, 645 microg/L; III = 32500 h*microg/L, 1300 microg/L). Whole blood clearance, steady state volume of distribution, and beta half-life were independent of dose and higher than published reports from other populations: 0.420 L/h/kg, 5.91 L/kg, and 17.3 h, respectively. These data show patients with acute severe TBI demonstrate a more rapid clearance and a larger distribution volume of CsA. Pharmacokinetic parameters derived from this study will guide dosing strategies for future prospective clinical trials evaluating CsA therapy following acute TBI.
authors.affiliation: Department of Pharmaceutical Sciences, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0509, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Empey
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
authors.forename: Byron
authors.initials: B
authors.lastname: Young
authors.forename: Margaret Bonnie
authors.initials: MB
authors.lastname: Rosbolt
authors.forename: Jimmi
authors.initials: J
authors.lastname: Hatton
mesh_terms: D000208:Acute Disease / Q000628:therapy; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015331:Cohort Studies; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000494:pharmacology; D010919:Placebos; D011446:Prospective Studies; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010919:Placebos; D016572:Cyclosporine