On the population pharmacokinetics and the enterohepatic recirculation of total ezetimibe

Abstract

Ezetimibe is a potent cholesterol absorption inhibitor, with an erratic pharmacokinetic (PK) profile, attributed to an extensive enterohepatic recirculation (EHC). The aim of this study was to develop a population PK model able to adequately characterize the complex distribution processes of total ezetimibe. The analysis was performed on the individual concentration-time data obtained from 28 healthy subjects who participated in a bioequivalence study comparing two oral ezetimibe formulations. The population PK analysis was performed using nonlinear mixed effect modeling, where different EHC models were developed and evaluated for their performance. Total ezetimibe pharmacokinetics was best described by a four-compartment model featuring EHC through the inclusion of an additional gallbladder compartment, which was assumed to release drug at specific time-intervals consistent with food intake. The final PK model was able to adequately estimate the population pharmacokinetic parameters and to allow for a formal characterization of the pharmacokinetic profile and the secondary peaks due to enterohepatic recirculation.

Population pharmacokinetics and enterohepatic recirculation of hyzetimibe and its main metabolite in Chinese healthy subjects

“…Data obtained from the BE study were pooled together setting period and treatment effects as potential covariates in the final dataset. Similar methodologies in the PK analysis have been suggested in previously published works 17,19 . The results showed that these 2 factors had no significant effect on the PK of HS‐25 and M1.…”

“…More often, a GB compartment was included in the model, and the GB compartment was usually connected to the GI compartment or the central compartment (parent drug and/or metabolites). Several methods have been reported to represent the periodical change between the GB compartment and the GI or central compartment, such as a sine function, 16 first‐order release, zero‐order release and a bolus 15,17,18 . In this study, different structure models were investigated.…”

“…in previously published works. 17,19 The results showed that these 2 factors had no significant effect on the PK of HS-25 and M1. We also tested adding interoccasional variability on residual errors, but this did not improve the model fitting, either.…”

“…The red area shows the 95% confidence interval of the predicted medians, and the blue areas are the 95% confidence intervals of the predicted 5th and 95th percentiles compartment, such as a sine function, 16 first-order release, zero-order release and a bolus. 15,17,18 In this study, different structure models were investigated. The common 1-or 2-compartment model, which did not include first-pass metabolism in the gut and EHC failed to describe the PK curves of both HS-25 and M1 (data not shown).…”

A Continuous Intestinal Absorption Model to Predict Drug Enterohepatic Recirculation in Healthy Humans: Nalbuphine as a Model Substrate

“…20 Other models may include time delays 21 or modeling biliary secretion with a sine function. 22 Models that include explicit gall bladder compartments with filling and emptying functions have also been reported. 23,24 We have previously published continuous intestinal absorption models for human and rat.…”