Background Physiologically based pharmacokinetic (PBPK) modeling offers a comprehensive framework for predicting the drug disposition in patients with liver cirrhosis. It enables the precise prediction of the pharmacokinetics (PK) across different stages of liver cirrhosis, supporting the informed dose decisions where clinical data is limited or clinical trials are ethically challenging. Methodology The current review compiles all the data from the published PBPK models related to liver cirrhosis, highlighting both drug–specific and system–specific input parameters as well as the model evaluation criteria. A systematic search across three scientific databases was employed to identify studies that met the predefined inclusion and exclusion criteria. The reported pathophysiological changes in liver cirrhosis, i.e., altered hepatic clearance, portal blood flow, serum proteins (albumin and alpha 1–acid glycoprotein) levels, and the enzymatic activity (reduced CYP450 enzyme abundance), were thoroughly analyzed. Results The drug exposure in liver cirrhosis varied from Child–Pugh (CP) A to C. Several drugs, such as repaglinide, clozapine, sildenafil, midazolam, and omeprazole, showed up to 9–fold increase in AUC in CP–B and C patients. Such changes were due to impaired hepatic metabolism, especially involving the CYP450 enzyme, highlighting the need for dose adjustment and close monitoring. In contrast, some drugs, such as nicardipine, hydroxychloroquine, ondansetron, and temocaprilat, exhibited decreased exposure, which was liable to compromise efficacy and thus required dosage adjustments. Moreover, apixaban, metformin, efavirenz, and ticagrelor depicted minimal or no PK changes, indicating no need for tailoring of dosage regimens. These varied PK responses emphasized the importance of individualized dosing strategies in liver cirrhosis patients. Conclusion This review provides a comprehensive summary of PBPK models developed for liver cirrhosis, highlighting the integration of drug–specific physiological changes. These alterations impact the drug clearance, portal blood flow, and exposure; therefore, a thorough understanding of these models may enhance clinical decision–making for practitioners regarding personalized dosing in patients with liver cirrhosis. Key Points • Liver cirrhosis is a progressive condition characterized by structural and functional alterations that profoundly impact the pharmacokinetics of drugs metabolized by the liver. • The current review highlights the use of physiologically based pharmacokinetic (PBPK) models in liver cirrhosis, evaluating the drug–specific predictions through predicted/observed ratios (R ratio) across CP classes relative to healthy subjects. • This study has paved the way for future research in developing the mechanistic PBPK models that may capture disease–specific changes, aiming to optimize drug dosing strategies in different stages of cirrhosis.

A Critical Review of Physiologically Based Pharmacokinetic (PBPK) Models in Liver Cirrhosis

期刊论文
发表日期：

2025年10月11日

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Hafsa Hafsa,
Muhammad Fawad Rasool,
Faleh Alqahtani

摘要

Background

Physiologically based pharmacokinetic (PBPK) modeling offers a comprehensive framework for predicting the drug disposition in patients with liver cirrhosis. It enables the precise prediction of the pharmacokinetics (PK) across different stages of liver cirrhosis, supporting the informed dose decisions where clinical data is limited or clinical trials are ethically challenging.

Methodology

The current review compiles all the data from the published PBPK models related to liver cirrhosis, highlighting both drug–specific and system–specific input parameters as well as the model evaluation criteria. A systematic search across three scientific databases was employed to identify studies that met the predefined inclusion and exclusion criteria. The reported pathophysiological changes in liver cirrhosis, i.e., altered hepatic clearance, portal blood flow, serum proteins (albumin and alpha 1–acid glycoprotein) levels, and the enzymatic activity (reduced CYP450 enzyme abundance), were thoroughly analyzed.

Results

The drug exposure in liver cirrhosis varied from Child–Pugh (CP) A to C. Several drugs, such as repaglinide, clozapine, sildenafil, midazolam, and omeprazole, showed up to 9–fold increase in AUC in CP–B and C patients. Such changes were due to impaired hepatic metabolism, especially involving the CYP450 enzyme, highlighting the need for dose adjustment and close monitoring. In contrast, some drugs, such as nicardipine, hydroxychloroquine, ondansetron, and temocaprilat, exhibited decreased exposure, which was liable to compromise efficacy and thus required dosage adjustments. Moreover, apixaban, metformin, efavirenz, and ticagrelor depicted minimal or no PK changes, indicating no need for tailoring of dosage regimens. These varied PK responses emphasized the importance of individualized dosing strategies in liver cirrhosis patients.

Conclusion

This review provides a comprehensive summary of PBPK models developed for liver cirrhosis, highlighting the integration of drug–specific physiological changes. These alterations impact the drug clearance, portal blood flow, and exposure; therefore, a thorough understanding of these models may enhance clinical decision–making for practitioners regarding personalized dosing in patients with liver cirrhosis.

Key Points

• Liver cirrhosis is a progressive condition characterized by structural and functional alterations that profoundly impact the pharmacokinetics of drugs metabolized by the liver.

• The current review highlights the use of physiologically based pharmacokinetic (PBPK) models in liver cirrhosis, evaluating the drug–specific predictions through predicted/observed ratios (R ratio) across CP classes relative to healthy subjects.

• This study has paved the way for future research in developing the mechanistic PBPK models that may capture disease–specific changes, aiming to optimize drug dosing strategies in different stages of cirrhosis.