Assessment of the impact of dosing time on the pharmacokinetics/pharmacodynamics of prednisolone.

Prednisolone is widely used for the treatment of inflammation and auto-immune diseases. It exhibits nonlinear pharmacokinetics (PK); and its induced systemic effects (pharmacodynamics (PD)) are commonly evaluated with two biomarkers, cortisol and blood lymphocytes in plasma. Circadian patterns are observed in both biomarkers. Furthermore, the disease itself may show a circadian pattern. For example, in rheumatoid arthritis patients, better therapeutic outcomes have been reported when prednisolone was administered in the very early morning. The aim of this study is to evaluate the impact of dosing time on the PK/PD of prednisolone with a simulation approach using an interactive algorithm. A series of simulations were performed with either intravenous or oral administration of prednisolone or prednisone. The results showed that the initial or maximum concentration and trough concentration of total prednisolone were lower when the drug was administered in the early morning around 6 AM: . Oscillation patterns were observed in cumulative cortisol suppression (CCS) and alteration of total lymphocyte trafficking in blood. When the drug was given in the morning within the therapeutic dose range, or around 6 PM: for a small dose amount (<1 mg), the minimum CCS and maximum effect on lymphocytes were observed. These results indicated that the PK/PD of prednisolone are time- and dose-dependent, and suggested that it is necessary to consider the application of chronotherapy to achieve better clinical outcomes with fewer side effects of prednisolone, and a PK/PD simulation approach could provide a valuable tool to evaluate and predict time-dependency in the system.