Opportunities and Challenges of Hepatic Impairment Physiologically Based Pharmacokinetic Modeling in Drug Development—An IQ Perspective

PBPK models are gaining special interest as a drug development tool to estimate the effect of intrinsic and extrinsic factors on drug pharmacokinetics. The IQ Consortium Clinical Pharmacology Organ Impairment Working Group conducted a survey across IQ Consortium member pharmaceutical companies to understand current practices on how PBPK is used in understanding the effect of hepatic impairment (HI) on drug disposition and its impact on clinical development. Responses from 21 participants indicated that most organizations (~86%) are already using PBPK models for HI assessment. The survey results indicate that PBPK models have been influential in optimizing the design of dedicated HI study with 57% of respondents using PBPK models to inform the design elements of dedicated HI studies, and the majority of these respondents using the PBPK model to support internal decision making regarding the HI study. Additionally, the PBPK model was used by 62% of the respondents to predict drug plasma protein binding. Despite common usage of the PBPK models by drug developers, 14.3% of the respondents discussed their PBPK modeling strategy with regulatory agencies with only two cases where the regulators accepted the PBPK model. In conclusion, although the use of PBPK models to support regulatory decisions regarding drug use in HI is currently limited, its future is promising, and the success of such models needs collaboration between regulators and drug developers to shrink the knowledge gap in the use of PBPK as an impactful tool for drug development in patients with HI.