Journal Article

Population Pharmacokinetics and Pharmacodynamics with Enterohepatic Recirculation of Co-Medication of Rosuvastatin and Ezetimibe

An, Hyungmi, Shin, Dongseong

2025

Overview

Combination therapy with rosuvastatin and ezetimibe is generally administered to patients with high cardiovascular risk. The objective of this study was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the interaction between rosuvastatin and ezetimibe that incorporates enterohepatic recirculation (EHC). Concentration-time data were obtained from a two-part, open-label, multiple-dose crossover, drug interaction study. In total, 50 healthy male subjects received both monotherapy and co-therapy (Part A: rosuvastatin and co-therapy; Part B: ezetimibe and co-therapy). Rosuvastatin (20 mg) or ezetimibe (10 mg) were administered once daily for 7 days as monotherapy or co-therapy. Plasma concentrations were measured for PK analysis until 72 h post-dose at steady state. The changes in low-density lipoprotein cholesterol (LDL-C) levels from baseline to steady state at 24 h after the last administration were measured. A population PK/PD model incorporating EHC was developed using Monolix 2024R1. Covariate effects were explored, and the final model was evaluated through goodness-of-fit diagnostics and visual predictive checks. Model-based simulations were conducted to compare the LDL-C lowering effects of monotherapy and co-therapy. A population PK/PD model was established using a two-compartment model for rosuvastatin and a four-compartment model for ezetimibe incorporating EHC via intermittent gallbladder emptying. No significant PK interaction was observed. An indirect response PD model reflected the independent LDL-C lowering effects of both drugs. Simulations showed LDL-C reductions of -51.0% (rosuvastatin), -25.3% (ezetimibe), and -60.7% (co-therapy), supporting the additive efficacy of co-therapy. EHC increased the exposure of total ezetimibe with limited LDL-C lowering effects. The overall PK interaction between rosuvastatin and total ezetimibe was not significant. The developed PK/PD model incorporating EHC successfully described the independent LDL-C lowering effects. These findings support the additive benefit of co-therapy of rosuvastatin and ezetimibe and may guide future research toward personalized lipid-lowering strategies.

• Publisher: Dove Medical Press Limited,Taylor & Francis Ltd,Dove Press,Dove,Dove Medical Press
• Subject: Adult / Anticholesteremic Agents - administration & dosage / Anticholesteremic Agents - pharmacokinetics / Anticholesteremic Agents - pharmacology / Cardiovascular disease / Cardiovascular diseases / Cholesterol / Cholesterol, LDL - blood / Combination therapy / Creatinine / Cross-Over Studies / Dosage and administration / Dose-Response Relationship, Drug / Drug dosages / Drug interaction / Drug Interactions / Drug Therapy, Combination / ezetimibe / Ezetimibe - administration & dosage / Ezetimibe - blood / Ezetimibe - pharmacokinetics / Ezetimibe - pharmacology / Gallbladder / Goodness of fit / Health risks / Healthy Volunteers / Humans / Lipids / Liver / Low density lipoprotein / Male / Middle Aged / modeling / Models, Biological / Original Research / Parameter estimation / Pharmacodynamics / Pharmacokinetics / Pharmacology, Experimental / Physiological aspects / Physiology / Plasma / Rosuvastatin / Rosuvastatin Calcium - administration & dosage / Rosuvastatin Calcium - blood / Rosuvastatin Calcium - pharmacokinetics / Rosuvastatin Calcium - pharmacology / Statins / Steady state / Therapy / Young Adult