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Hepatic Impairment Physiologically Based Pharmacokinetic Model Development: Current Challenges

  • Pharmacometrics and Quantitative System Pharmacology (S Woo, Section Editor)
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An Author Correction to this article was published on 26 October 2021

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Abstract

Purpose

This review summarizes the development processes of hepatic impairment (HI) PBPK models, examines current challenges, and proposes potential solutions.

Recent Findings

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.

Summary

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.

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References

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Author notes

  1. Beatrice Han and Agnes Han contributed equally.

Authors and Affiliations

  1. Washington University in St. Louis, St. Louis, MO, 63130, USA

    Agnes Nuo Han

  2. University of Pennsylvania, Philadelphia, PA, 19104, USA

    Beatrice Rae Han

  3. School of Pharmacy, Husson University, Bangor, ME, 04401, USA

    Tao Zhang & Tycho Heimbach

  4. MRL – Sterile & Specialty Products Group, Biopharmaceutics Merck & Co., Inc., 126 E Lincoln Avenue – RY80B, 1416E, Rahway, NJ, 07065, USA

    Tycho Heimbach

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  1. Agnes Nuo Han
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Han, A.N., Han, B.R., Zhang, T. et al. Hepatic Impairment Physiologically Based Pharmacokinetic Model Development: Current Challenges. Curr Pharmacol Rep 7, 213–226 (2021). https://doi.org/10.1007/s40495-021-00266-5

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