Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, 60800, Pakistan.
Drug Des Devel Ther. 2021 Mar 17;15:1195-1211. doi: 10.2147/DDDT.S297981. eCollection 2021.
The study was aimed to understand the underlying causes for the differences in propranolol pharmacokinetics (PK) between healthy and cirrhosis populations by using a systematic whole-body physiologically based pharmacokinetic (PBPK) model-building approach for suggesting model informed propranolol dosing in liver cirrhosis patients with different stages of disease severity.
A whole-body PBPK model was developed by using population simulator PK-Sim by using reported physicochemical and clinical data for propranolol in healthy and liver cirrhosis populations. The model evaluation was done by visual verification and comparison of PK parameters using their observed/predicted ratios (R).
The developed model has effectively described the disposition of propranolol after intravenous and oral application in healthy and liver cirrhosis populations. All the model predictions were comparable to the observed clinical data and the R for all the PK parameters were within a 2-fold range. A significant increase in plasma concentration of propranolol and decrease in drug clearance was observed in progressive stages of liver cirrhosis. The developed model after evaluation with the reported clinical PK data was used for suggesting model informed propranolol dosing in different stages of liver cirrhosis based on systemic unbound drug concentration.
The developed PBPK model has successfully described propranolol PK in healthy and cirrhosis populations after IV and oral administration. The evaluated PBPK propranolol-cirrhosis model can have many implications in predicting propranolol dosing in liver cirrhosis patients with different stages of disease severity.
本研究旨在通过采用系统的全身体生理药代动力学（PBPK）模型构建方法，了解健康人群和肝硬化人群之间普萘洛尔药代动力学（PK）差异的潜在原因，为不同疾病严重程度的肝硬化患者提供基于模型的普萘洛尔给药建议。
采用群体模拟器 PK-Sim，利用普萘洛尔在健康人群和肝硬化人群中的报告理化数据和临床数据，开发全身体 PBPK 模型。通过观察/预测比值（R）对 PK 参数进行视觉验证和比较，对模型进行评估。
所开发的模型能够有效地描述普萘洛尔在健康人群和肝硬化人群中静脉注射和口服给药后的处置情况。所有模型预测均与临床观察数据相当，所有 PK 参数的 R 值均在 2 倍范围内。随着肝硬化的进展，普萘洛尔的血浆浓度显著升高，药物清除率降低。在使用报告的临床 PK 数据进行评估后，所开发的模型用于根据系统未结合药物浓度建议不同阶段肝硬化的基于模型的普萘洛尔给药。
所开发的 PBPK 模型成功描述了普萘洛尔在健康人群和肝硬化人群中的 IV 和口服给药后的 PK 情况。评估后的 PBPK 普萘洛尔-肝硬化模型可以对不同疾病严重程度的肝硬化患者进行普萘洛尔给药预测。
