Dosing and safety of cyclosporine in patients with severe brain injury.

OBJECT: Cyclosporine neuroprotection has been reported in brain injury models but safety and dosing guidelines have not been determined in humans with severe traumatic brain injury (TBI). The purpose of this investigation was to establish the safety of cyclosporine using 4 clinically relevant dosing schemes.

METHODS

The authors performed a prospective, blinded, placebo-controlled, randomized, dose-escalation trial of cyclosporine administration initiated within 8 hours of TBI (Glasgow Coma Scale score range 4-8; motor score range 2-5). Four dosing cohorts (8 patients treated with cyclosporine and 2 receiving placebo treatment per cohort) received cyclosporine (1.25-5 mg/kg/day) or placebo in 2 divided doses (Cohorts I-III) or continuous infusion (Cohort IV) over 72 hours. Adverse events and outcome were monitored for 6 months.

RESULTS

Forty patients were enrolled over 3 years (cyclosporine cohorts, 24 male and 8 female patients; placebo group, 8 male patients). Systemic trough concentrations were below 250 ng/ml during intermittent doses. Higher blood concentrations were observed in Cohorts III and IV. There was no significant difference in immunological effects, adverse events, infection, renal dysfunction, or seizures. Mortality rate was not affected by cyclosporine administration, independent of dose, compared with placebo (6 of 32 patients receiving cyclosporine and 2 of 8 receiving placebo died, p>0.05). At 6 months, a dose-related improvement in favorable outcome was observed in cyclosporine-treated patients (p<0.05).

CONCLUSIONS

In patients with acute TBI who received cyclosporine at doses up to 5 mg/kg/day, administered intravenously, with treatment initiated within 8 hours of injury, the rate of mortality or other adverse events was not significantly different from that of the placebo group.