Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation

Background. The new oral microemulsion formulation of cyclosporine (Neoral(R)) possesses superior pharmacokinetics to the conventional formulation, Sandimmun (SIM), providing more complete and predictable absorption, and less pharmacokinetic variability. Methods. The safety and tolerability of Neoral(R), together with the incidence of acute rejection episodes and graft survival, were compared to the conventional cyclosporine formulation, SIM, in a prospective, randomized, double-blind multicenter trial. A total of 167 patients who received a first or second cadaveric renal transplant in 21 participating centers in six countries were randomized equally to two treatment groups and followed for three months after transplantation. Outcomes were analyzed across treatment, center and regional groups. In addition, a nested pharmacokinetic study was performed in four of these centers throughout the period of follow-up. Results. No difference was detected between the safety or tolerability of the two formulations. Kidney function and other laboratory parameters remained comparable in Neoral(R)- and SIM-treated patients throughout the study. However, the number of patients experiencing acute rejection was significantly reduced for the Neoral group (44.2% vs. 60.5%; P = 0.044), and significantly fewer patients experienced multiple episodes of rejection (12.8% vs. 22.2%, P = 0.028). The proportion of patients free of rejection at three months was significantly higher in patients treated with Neoral(R) than in those receiving SIM (Kaplan-Meier estimated probability of remaining rejection-free at 3 months = 55% for the Neoral(R) group, compared with 39% for the SIM group, P = 0.046, log rank test). Similar results were obtained when acute rejection, graft loss and death were used as a combined endpoint (Kaplan-Meier estimated probability for Neoral(R) group = 54%, compared with 38% for the SIM group, P = 0.047, log rank test). Comparison of results by center or regional groups did not show any significant treatment interaction. A nested pharmacokinetic evaluation (four centers; 28 subjects) showed that the bioavailability of cyclosporine from NeoralO(R) was significantly higher than from SIM at all assessment times. Specifically, at weeks 2, 4 to 6, and 12, dose-normalized AUC was 49%, 63% and 32% higher for Neoral(R). Dose-normalized peak cyclosporine blood concentrations and AUC stabilized by weeks 4 to 6 in patients receiving Neoral(R), whereas these values increased slowly in SIM-treated patients without reaching the levels achieved in the Neoral(R) group. Conclusions. These results suggest that the superior pharmacokinetic characteristics of the microemulsion formulation of cyclosporine lead to more efficient immunosuppression during the first critical months after transplantation, without a deleterious impact on clinical safety.