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<p>Doxazosin, a selective α<sub>1</sub>-adrenergic receptor antagonist, is widely used to treat hypertension and benign prostatic hyperplasia and is available in immediate-release (IR) and extended-release (ER) formulations. However, quantitative tools for predicting pharmacokinetic (PK) differences between formulations and changes in drug exposure in patients with impaired liver function remain unestablished. Therefore, this study aims to develop a physiologically based pharmacokinetic (PBPK) model for doxazosin IR and ER formulations and to predict PK patterns under various dosing scenarios and levels of liver disease severity. The model was developed using PK-Sim® and subsequently validated and optimized using clinical data obtained from multiple published sources. Key parameters included the physicochemical properties of doxazosin, absorption and metabolism coefficients, and organ-specific distribution coefficients. The model also incorporated physiological changes associated with liver disease, such as altered blood flow and enzyme activity. The model prediction results showed a significant difference in maximum plasma concentration (<i>C</i><sub>max</sub>) and time to reach <i>C</i><sub>max</sub> (<i>T</i><sub>max</sub>) between the IR and ER formulations after single dose administration. Additionally, the variation between maximum plasma concentration at steady-state (<i>C</i><sub>peak</sub>) and minimum plasma concentration at steady-state (<i>C</i><sub>trough</sub>) was greater for the IR formulation in multiple doses. However, the area under the plasma concentration curve (AUC) and systemic clearance (CL/F) were similar between the IR and ER formulations, accounting for the dose. In patients with liver disease, plasma doxazosin concentrations increased following the Child–Pugh (CP) grade, with doxazosin exposure rising progressively from CP-A to CP-C. The PBPK model developed in this study serves as a practical tool for quantitatively predicting the PK of doxazosin across different formulations and varying degrees of liver impairment. It holds potential for supporting the development of patient-tailored treatment strategies in the future.</p>

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Physiologically based pharmacokinetic modeling of immediate-release and extended-release formulations of doxazosin, an alpha-1 adrenergic receptor antagonist, with model simulations for patients with liver disease

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • Seung-Hyun Jeong,
  • Ji-Hun Jang,
  • Ho-Suk Kang

摘要

Doxazosin, a selective α1-adrenergic receptor antagonist, is widely used to treat hypertension and benign prostatic hyperplasia and is available in immediate-release (IR) and extended-release (ER) formulations. However, quantitative tools for predicting pharmacokinetic (PK) differences between formulations and changes in drug exposure in patients with impaired liver function remain unestablished. Therefore, this study aims to develop a physiologically based pharmacokinetic (PBPK) model for doxazosin IR and ER formulations and to predict PK patterns under various dosing scenarios and levels of liver disease severity. The model was developed using PK-Sim® and subsequently validated and optimized using clinical data obtained from multiple published sources. Key parameters included the physicochemical properties of doxazosin, absorption and metabolism coefficients, and organ-specific distribution coefficients. The model also incorporated physiological changes associated with liver disease, such as altered blood flow and enzyme activity. The model prediction results showed a significant difference in maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) between the IR and ER formulations after single dose administration. Additionally, the variation between maximum plasma concentration at steady-state (Cpeak) and minimum plasma concentration at steady-state (Ctrough) was greater for the IR formulation in multiple doses. However, the area under the plasma concentration curve (AUC) and systemic clearance (CL/F) were similar between the IR and ER formulations, accounting for the dose. In patients with liver disease, plasma doxazosin concentrations increased following the Child–Pugh (CP) grade, with doxazosin exposure rising progressively from CP-A to CP-C. The PBPK model developed in this study serves as a practical tool for quantitatively predicting the PK of doxazosin across different formulations and varying degrees of liver impairment. It holds potential for supporting the development of patient-tailored treatment strategies in the future.