Dosing and safety of cyclosporine in patients with severe brain injury

Abstract

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.

Conflict of interest statement

Disclaimer: The authors do not report any conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Figures

Fig. 1

Graph showing the percentage of patients who experienced serious adverse events. The majority of the 32 cyclosporine-treated patients had no serious adverse event, and there was no significant difference in the incidence between the placebo controls and treated patients.

Fig. 2

Graph showing the number of patient deaths in each group. There was no effect of cyclosporine dose on mortality end points. There were 6 deaths in the cyclosporine-treated group and 2 deaths in the placebo group.

Fig. 3

Graph showing the incidence of infections. No clinical safety concerns were observed in the cyclosporine-treated patients. The incidence of infectious complications did not differ between dosing groups or between cyclosporine-treated patients and placebo controls. UTI = urinary tract infection.

Fig. 4

Graph showing the results of liver function tests. No significant effect of cyclosporine treatment on liver function was observed. During the 1st week after injury, rises in bilirubin were observed in both placebo controls and cyclosporine-treated patients. ALT = alanine transaminase; AP = alkaline phosphatase; AST = aspartate transaminase; GGT = gamma glutamyl transferase.

Fig. 5

Graphs of pharmacokinetic modeling. Observed (squares) and predicted (lines) cyclosporine whole blood concentrations in a representative patient at each dosing level. (See Table 1 for the cyclosporine doses.) Conc = Concentration.

Fig. 6

Graph showing the percentages of cyclosporine-treated and control patients with favorable GOS and GOSE scores. Data were examined for trends associated with cyclosporine treatment effect on functional outcome at 3 and 6 months following injury. There was no statistically significant difference in GOS scores between the surviving patients treated with cyclosporine and placebo controls.

Fig. 7

Graph showing percentages of patients with favorable GOS and GOSE scores stratified by cohort. Data were examined for functional outcome trends in response to differing dosing strata for cyclosporine. Increasing doses showed a probability of favorable outcome. The patients in Cohort IV, who were treated with the continuous infusion dosing paradigm, had the most improved scores (p