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 (Ne oral(R)) possesses superior pharmacokinetics to the conventional formu lation, Sandimmun (SIM), providing more complete and predictable absor ption, and less pharmacokinetic variability. Methods. The safety and t olerability of Neoral(R), together with the incidence of acute rejecti on episodes and graft survival, were compared to the conventional cycl osporine formulation, SIM, in a prospective, randomized, double-blind multicenter trial. A total of 167 patients who received a first or sec ond cadaveric renal transplant in 21 participating centers in six coun tries were randomized equally to two treatment groups and followed for three months after transplantation. Outcomes were analyzed across tre atment, center and regional groups. In addition, a nested pharmacokine tic 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 lab oratory parameters remained comparable in Neoral(R)- and SIM-treated p atients throughout the study. However, the number of patients experien cing acute rejection was significantly reduced for the Neoral group (4 4.2% vs. 60.5%; P = 0.044), and significantly fewer patients experienc ed multiple episodes of rejection (12.8% vs. 22.2%, P = 0.028). The pr oportion of patients free of rejection at three months was significant ly higher in patients treated with Neoral(R) than in those receiving S IM (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 a cute rejection, graft loss and death were used as a combined endpoint (Kaplan-Meier estimated probability for Neoral(R) group = 54%, compare d 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 tre atment interaction. A nested pharmacokinetic evaluation (four centers; 28 subjects) showed that the bioavailability of cyclosporine from Neo ralO(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 r eceiving Neoral(R), whereas these values increased slowly in SIM-treat ed patients without reaching the levels achieved in the Neoral(R) grou p. Conclusions. These results suggest that the superior pharmacokineti c characteristics of the microemulsion formulation of cyclosporine lea d to more efficient immunosuppression during the first critical months after transplantation, without a deleterious impact on clinical safet y.