Physiologically based pharmacokinetic modeling to characterize enterohepatic recirculation and predict food effect on the pharmacokinetics of hyzetimibe.

BACKGROUND AND OBJECTIVE

Hyzetimibe is a cholesterol absorption inhibitor indicated for the treatment of hypercholesterolemia. This study aims to describe the multiple-peak pharmacokinetics (PK) of hyzetimibe and its active metabolite M1 through physiologically-based pharmacokinetic (PBPK) modeling, and to compare the model predictions of a virtual food effect study with the results of a clinical food effect study.

METHODS

The plasma concentration data used for PBPK modeling were obtained from a single-dose, two-period crossover bioequivalence study in the fasted state. Advanced Compartmental Absorption and Transit model was used for absorption. Enterohepatic recirculation process was modeled by changing the gut physiological state from fasted to fed at meal time. Based on the established PBPK models, a virtual food effect study was simulated. A clinical food effect study was used for model external validation.

RESULTS

PK profiles of hyzetimibe and M1 under fasting condition could be well described by the PBPK model, and the errors of C, AUC, and AUC were within the two-fold range. Simulated geometric mean ratios (GMRs, fed/fasted) showed that a high-fat breakfast slightly affected the PK of hyzetimibe, expressed as increased C of hyzetimibe (130.6%). Simulated GMRs and 90% confidence intervals of AUC were within the preset bioequivalent range. The results of the simulated virtual food effect trial were consistent with those of the clinical food effect trial.

CONCLUSIONS

The established PBPK model could describe the concentration-time profiles of hyzetimibe and M1 well with good prediction performance. A fully mechanistic model of enterohepatic recirculation warrants further investigation.