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

Abstract

Objective: 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).

Methods: 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.

Results: 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.

Conclusion: 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.