Circadian pharmacokinetics and limited sampling strategy of everolimus in heart transplant patients

Objective: To evaluate circadian changes in everolimus (EVL) pharmacokinetics and to identify the time point of blood sampling with the strongest correlation with the area under the blood concentrationtime curve (AUC) of EVL in heart transplant patients. Methods: Heart transplant patients receiving the same dose of EVL twice a day were reviewed. In 28 patients enrolled, whole blood samples were collected before (C₀), and 1, 2, 4, 6, 8, and 12 hours after each administration of EVL. Blood concentrations of EVL were compared between active (9:00 AM to 9:00 PM) and resting periods (9:00 PM to 9:00 AM). Results: AUC_0-4h, peak concentration (C_max), C_max/minimum concentration, and peak-trough fluctuation in the resting period were significantly lower than those in the active period (p = 0.008, 0.017, 0.022, and 0.011, respectively). Halflife and mean residence time were significantly longer in the resting period than in the active period (p = 0.002 and 0.002, respectively). AUC_0-12h in the active period was similar (p = 0.154) and correlated with that in the resting period (r² = 0.93). Two-point blood samplings, C₀ and C₂, correlated more strongly with AUC_0-12h for EVL, compared with C₀ alone (0.92 vs. 0.79, respectively, for r² in the active period). Conclusions: EVL pharmacokinetics showed circadian changes, suggesting delayed absorption and decreased metabolic activity at rest. However, the circadian changes did not affect AUC_0-12h. A 2-time-point model that included C₀ and C₂ was more accurate for predicting the AUC_0-12h of EVL than C₀ alone in heart transplant patients.