Hyzetimibe

Hyzetimibe (HS‐25), a new drug approved for hypercholesterolaemia, exhibits obvious enterohepatic recirculation (EHC) after oral administration. Up to now, little is known about the kinetics of HS‐25. Therefore, we performed this population pharmacokinetic (PopPK) analysis aiming to describe the PK behaviour of HS‐25 and its main metabolite (M1), and to identify significant covariates contributing to the variability.

The plasma concentration data used for modelling were obtained from an open‐label, single‐dose, randomized, 2‐period crossover bioequivalence study. PopPK modelling was performed with NONMEM 7.4.1 using nonlinear mixed effect modelling approach. Goodness of fit plots, bootstrap and visual predictive check were used for model internal validation. Data from another study were used for external validation.

Data from 16 male and 8 female subjects were used in the PopPK analysis. HS‐25 and M1 concentrations in the modelling cohort were well described by a 1‐compartment model incorporating first‐pass metabolism and a gallbladder compartment, accounting for the EHC process. The release kinetic of gall was mimicked by a first‐order constant plus a switch on/off effect. Body weight was identified as a significant covariate effecting on the clearance and apparent distribution volume of HS‐25, as well as , the transfer rate from metabolite compartment to gallbladder compartment. Internal and external validation demonstrated an acceptable predictive ability of the final model.

We present the first PopPK model describing HS‐25 and M1 concentrations simultaneously, with the EHC process considered. The modelling and simulation results could provide reference for the clinical use of HS‐25.

Background: Hyzetimibe is a new compound belonging to a novel class of selective cholesterol absorption inhibitors. A simple, highly sensitive LC–MS/MS method has been developed for the quantification of hyzetimibe and its main active metabolite, hyzetimibe-glucuronide, in human plasma. Results: Analytical samples were prepared using a protein precipitation method coupled with a concentration process. The linearity of this method was established for concentrations in the ranges of 0.05–50 and 0.5–500 ng/ml for hyzetimibe and hyzetimibe-glucuronide, respectively. The accuracy and precision of the method varied from 97.9 to 105% and 2.6 to 7.4%, respectively. Conclusion: This study represents the first reported example of an LC–MS/MS assay for the simultaneous quantification of hyzetimibe and its main active metabolite, hyzetimibe-glucuronide, in human plasma. Furthermore, this method has been successfully applied to a PK study.