Effect of Meal Timings and Meal Content on the AUC0-12h of Mycophenolic Acid: A Simulation Study.

Meal timings and content related to gallbladder emptying in the enterohepatic circulation are important for explaining the high variability in mycophenolic acid exposure. The limited sampling strategy (LSS) was established to estimate the area under the plasma concentration-time curve from time 0 to 12 hours (AUC0-12h ) of mycophenolic acid in therapeutic drug monitoring. The aim of this study is to investigate the effect of meal timings and content on the AUC0-12h of mycophenolic acid and to assess the influence of meals on LSS. A mycophenolic acid pharmacokinetic model with a mechanism-based enterohepatic circulation process was employed to perform simulations under various assumed meal scenarios. The simulations were compared to evaluate the effect of meal timings and meal content on mycophenolic acid AUC0-12h . Monte Carlo simulations were performed using the meal parameter with the greatest impact on mycophenolic acid AUC0-12h as a variable. The corresponding LSS equations were established, and the predictive performance was assessed. Both the meal timings and meal content affected the mycophenolic acid AUC0-12h , and the postdose fasting period had the greatest impact. The predictive performance of the LSS is sensitive to the postdose fasting period. Therefore, meal timings may improve the estimation of mycophenolic acid AUC0-12h and the efficacy of therapeutic drug monitoring.