Within-Day Consistency in Cyclosporine Pharmacokinetics from a Microemulsion Formulation in Renal Transplant Patients

Abstract

A new microemulsion formulation of cyclosporine (Sandimmune Neoral) was compared to the commercially available formulation (Sandimmune) in 11 stable renal transplant patients with regard to the consistency in cyclosporine pharmacokinetics between a daytime fasting, and a nighttime nonfasting administration. Daily cyclosporine doses were individualized and administered in equal, divided doses every 12 h as soft gelatin capsules; doses were kept constant throughout the study. Serial blood samples were obtained over a 24-h period (two consecutive dosing intervals) at steady-state for each formulation, and cyclosporine concentrations were determined in whole blood by a specific radioimmunoassay method. Within-formulation consistency in pharmacokinetic parameters between the daytime and nighttime administrations was assessed in terms of bioequivalence criteria. Following the mg-to-mg conversion from the commercial to the microemulsion formulation, area under the curve (AUC) was increased on average by 30% due to absorption-related pharmacokinetic differences, while trough concentrations remained in the therapeutic range. Within each formulation, AUC was bioequivalent when comparing the daytime fasting to the nighttime nonfasting administration. For the commercial formulation, however, there was considerable variation in absorption rate, dampening of peak-trough fluctuation, and elevation of trough concentration following the nighttime nonfasting dose. By contrast, the microemulsion exhibited a more stable concentration-time profile over the two dosing intervals, with bioequivalence in peak-trough fluctuation and trough concentrations. Hence, the steady-state pharmacokinetics of cyclosporine from the microemulsion formulation exhibit greater within-day consistency compared to the commercial formulation in stable renal allograft recipients.