CYCLOSPORINE DISPOSITION AND METABOLITE PROFILES IN RENAL-TRANSPLANT PATIENTS RECEIVING A MICROEMULSION FORMULATION

Several lines of evidence suggest that cyclosporine may undergo prehepatic metabolism, the possible contribution of which to the overall biotransformation of the drug is, however, unclear. A recently developed oral formulation of cyclosporine, Sandimmune Neoral, which incorporates the drug in a microemulsion preconcentrate, exhibits a faster rate of absorption and a shorter residence time in the gastrointestinal tract compared to the currently marketed formulation, Sandimmune. If prehepatic metabolism plays an important role, this could, theoretically, have an impact on the metabolite profile from the microemulsion formulation. Therefore, the pharmacokinetics of cyclosporine and its major metabolites were assessed in 13 clinically stable renal transplant patients receiving the commercial and the new formulations at steady state. Whole blood samples were collected over a dosing interval and analyzed by high-performance liquid chromatography (HPLC). Model-fitting of the concentration-time profiles of the parent compound indicated that while the systemic disposition was similar between formulations, absorption-related pharmacokinetic differences were evident. This was manifested in patients at steady state as shorter lag time and faster rate of absorption of the parent compound from the microemulsion formulation. The metabolite-to-parent area under the curve (AUC) ratios for the major metabolites AM1, AM4N, and AM9 were comparable between formulations. Specifically for metabolites AM1 and AM9, which predominated in whole blood and could, therefore, be fully characterized, the area ratios were bioequivalent when comparing the two formulations. Hence, absorption-related differences between the two oral formulations does not affect the systemic metabolite profile during steady-state administration in patients.