Hepatic Impairment Physiologically Based Pharmacokinetic Model Development: Current Challenges

This review summarizes the development processes of hepatic impairment (HI) PBPK models, examines current challenges, and proposes potential solutions. Because hepatic impairment can significantly alter a patient’s physiology, HI PBPK models must consider complex in vivo processes leading to potential changes in PK parameters. Adjustments need to be made to absorption, distribution, metabolism, and elimination parameters. Multiple studies already include changes in levels of CYP enzymes, UGTs, transporters, shunting, and protein binding in their HI models. However, despite recent progress, HI PBPK models face multiple challenges and may overpredict drug exposure with increasing severity of liver dysfunction. Foremost among these challenges is the use of the Child–Pugh scoring system in designing HI PBPK models. Furthermore, most HI PBPK models do not account for changes in certain drug parameters, potentially skewing resulting predictions. Ultimately, limitations with PBPK models can be traced to the scarcity of existing HI PBPK models and clinical data. Filling in this knowledge gap is critical to best support safe drug dosing adjustments for hepatically impaired patients. Recent advancements have enhanced the predictive power of HI PBPK models, enabling accurate reflections of clinical trials. However, significant obstacles in developing accurate PK predictions remain, especially for severe impairment.