Development of Sang-35: a cyclosporine formulation bioequivalent to Neoral.
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 Sang-35 (AUC0-infinity: 13,900 +/- 2470 micrograms.h.L-1, mean +/- standard deviation (SD)) and of Neoral (AUC0-infinity: 14,000 +/- 2900 micrograms.h.L-1) resulted in equal areas-under-the-time-concentration curve (AUC0-infinity). 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), AUC0-12 h after Sang-35 was, as expected, significantly higher than that after Sandimmune (4550 +/- 1858 vs 3468 +/- 1402 micrograms.h.L-1, p < 0.01). Sang-35 and Neoral resulted in equivalent cyclosporine AUC0-12 h values (4120 +/- 1508 and 4377 +/- 1579 micrograms.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.
First
M R
MR
University of Cincinnati Medical Center, OH 45267-0585, USA.
Alloway
R
R
Schroeder
T J
TJ
D000284:Administration, Oral; D000328:Adult; D044383:Black People; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004304:Dosage Forms; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D013810:Therapeutic Equivalency; D001741:Black or African American
D004304:Dosage Forms; D007166:Immunosuppressive Agents; D016572:Cyclosporine