Development of Sang-35: A cyclosporine formulation bioequivalent to Neoral

Abstract

During a research program, SangStat Medical Corporation developed more than 270 oral cyclosporine formulations. On the basis of animal and clinical trials, Sang-35 was chosen for clinical development, and bioequivalence with the cyclosporine microemulsion Neoral was established. In a cross-over study involving 36 healthy male volunteers, single 500 mg cyclosporine doses of Sane-35 (AUC(0-∞): 13900 ± 2470 μg·h·L-1, mean ± standard deviation (SD)) and of Neoral (AUC(0-∞): 14000 ± 2900 μg·h·L-1) resulted in equal areas-under-the-time-concentration curve (AUC(0-∞)). Sang-35 and Neoral were also bioequivalent in healthy male subjects after high-fat meals as well as in female and African-American subjects. In stable kidney transplant patients (n = 12) receiving a mean (± SD) cyclosporine dose of mg/d (3.6 + 1.6 mg/kg/d), AUC(0-12 h) after Sang-35 was, as expected, significantly higher than that after Sandimmune (4550 ± 1858 vs 3468 ± 1402 μg·h·L-1 p < 0.01). Sang-35 and Neoral resulted in equivalent cyclosporine AUC(0-12 h) values (4120 ± 1508 and 4377 ± 1579 μg·h·L-1, respectively) in stable kidney transplant patients (dose: 293 ± 114 mg/d or 3.7 ± 1.5 mg/kg/d, n = 32). In an additional study, 42 stable kidney graft patients were switched from Sandimmune to Sang-35. Based on a conversion strategy targeting AUC equivalence, only one dose adjustment was required in 55% of the patients, and 95% of patients (40 of 42) needed three or fewer dose adjustments. The mean Sang-35 dose was 7% lower than the mean Sandimmune dose. During the studies, Sang-35 and Neoral exhibited similar safety and tolerability profiles. It is concluded that Sang-35 and Neoral are bioequivalent and that patients can safely and easily be switched from Neoral or, in combination with dose adjustment, from Sandimmune to Sang-35.