Time-dependent disposition of cyclosporine after pancreas transplantation, and application of chronopharmacokinetics to improve immunosuppression.

We studied the circadian influences on cyclosporine pharmacokinetics in five recipients of pancreatic allografts. Results from these patients demonstrate a slightly increased area under the concentration-time curve (p = 0.156) resulting from decreased apparent clearance during the resting (PM) versus activity (AM) period (p = 0.199). A significant delay in mean residence time was observed after the PM dose (p = 0.039), and the PM area under the moment curve was larger than the AM value (p = 0.063). We propose three chronopharmacokinetic dosing methods that alter either the PM dose administration time or redistribute the daily dose to produce equal exposure to cyclosporine during the active and resting periods. These trends and differences suggest that more sophisticated time-dependent cyclosporine dosing methods are needed to balance AM and PM drug exposure and thereby improve immunosuppression.