Reduced intrapatient variability of cyclosporine pharmacokinetics in renal transplant recipients switched from oral Sandimmune to Neoral

Sixty-six renal transplant patients maintained on Sandimmune®, the traditional formulation of cyclosporine, participated in an open-label, sequential trial to compare intrapatient variability in drug exposure before and after a switch to Neoral®. Three 12-hour cyclosporine pharmacokinetic profiles were obtained over approximately 6 weeks while patients were receiving Sandimmune. Patients were then switched to Neoral, with the dose adjusted as necessary to maintain target trough blood cyclosporine concentrations. At approximately 4 and 6 weeks postconversion, 2 additional pharmacokinetic profiles were obtained. Key pharmacokinetic variables analyzed were area under the concentration-time curve (AUC), maximum concentration (C(max)), and predose trough concentration (C₀). Intrapatient variability in drug exposure for dose-normalized mean AUC, C(max), and C₀ was significantly reduced with Neoral, with 50 (76%), 57 (86%), and 45 (68%) patients experiencing reduced variability in AUC, C(max) and C₀, respectively (P < 0.001). Additionally, the total exposure to cyclosporine was more predictable from the trough level of cyclosporine with Neoral; the relationship between AUC and C₀ was 0.81 for Neoral at both pharmacokinetic profiling time points but ranged from 0.49 to 0.69 for the 3 Sandimmune time points. The large reductions in intrapatient variability of pharmacokinetic variables for cyclosporine provided by Neoral indicate an improvement in the consistency of drug exposure, which may translate into important clinical benefits.