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Controversies exist over the role of cyclosporine (CYA) metabolites in terms of efficacy and toxicity, and the potential impact of formulation changes on the metabolite pharmacokinetic profile. To evaluate formulation effect on metabolite pharmacokinetic profiles between two CYA formulations (Sang-35 and Neoral), whole blood samples were analyzed by HPLC for concentrations of the parent compound, CYA, and metabolites, AM1, AM9, AM4N, and AM1c. Ten renal transplant recipients participated in a 2-treatment, 3-period, cross-over study to assess bioequivalence. Pharmacokinetic parameters were determined by analysis of concentrations at time 0, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours after a steady state morning dose. A paired t-test determined the variance between formulation Cmax, Tmax. AUC for CyA and its metabolites.
There were no statistically significant differences between formulations for pharmacokinetic parameters measured by HPLC for CyA, AMI, or AM9. Only 5 patients had detectable concentrations of both formulations for AM4N, and two patients for AM1c. The concentrations observed were similar, and reflect expected low concentrations of these metabolites. Bioequivalence between CyA formulations Sang-35 and Neoral is established with regard to CyA and metabolites AMI, AM9, AM4N. and AM1c in stable renal transplant recipients. Study funded in part by SangStat Medical Corporation.