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Utility of physiologically based pharmacokinetic (PBPK) modeling in oncology drug development and its accuracy: a systematic review

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Abstract

Purpose

Physiologically based pharmacokinetic (PBPK) modeling, a mathematical modeling approach which uses a pharmacokinetic model to mimick human physiology to predict drug concentration–time profiles, has been used for the discover and development of drugs in various fields, including oncology, since 2000. There have been a few general review articles on the utilization of PBPK in the development of oncology drugs, but these do not include an evaluation of model prediction accuracy. We therefore conducted a systematic review to define the accuracy of PBPK model prediction and its utility throughout all the developmental phases of oncology drugs.

Methods

A systematic search was performed in the PubMed, PubMed Central and Cochrane Library databases from 1980 to February 2017 for articles (1) written in English, (2) focused on oncology or antineoplastic or anticancer drugs, tumor or cancer or anticancer drugs listed in the U.S. National Institutes of Health and (3) involving a PBPK model. The absolute-average-folding-errors (AAFEs) of the area under the curve (AUC) between predicted and observed values in each article were calculated to assess model prediction accuracy.

Results

Of the 2341 articles initially identified by our search of the databases, 40 were included in the review analysis. These articles reported on six types of studies, i.e. in vivo (n = 4), first-in-human (n = 5), phase II/III clinical trials (n = 9), organ impairment (n = 3), pediatrics (n = 4) and drug–drug interactions (n = 15). AAFEs of the predicted AUC for all groups of studies were within 1.3-fold of each other despite variations in experimental methodologies.

Conclusion

PBPK modeling is a potential tool which can be effectively applied throughout all phases of oncology drug development. The number of experimental animals and human participants enrolled in the studies can be reduced using PBPK modeling and PBPK-population-PK modeling. The limited number of publications of unsuccessful model application to date may contribute to bias toward the usefulness of modeling.

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Authors and Affiliations

  1. Department of Clinical Product Development, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Teerachat Saeheng & Juntra Karbwang

  2. Leading Program, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Teerachat Saeheng

  3. Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12121, Thailand

    Kesara Na-Bangchang

  4. Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12121, Thailand

    Kesara Na-Bangchang

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  1. Teerachat Saeheng
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TS was responsible for data collection, selection of the published articles, data analysis and data interpretation and prepared the draft manuscript. KN and JK were responsible for the selection of the published articles, concept of data analysis, data interpretation and revision of the manuscript.

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Correspondence to Juntra Karbwang.

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Teerachat Saeheng, Kesara Na-Bangchang and Juntra Karbwang have no conflicts of interest in this review.

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Saeheng, T., Na-Bangchang, K. & Karbwang, J. Utility of physiologically based pharmacokinetic (PBPK) modeling in oncology drug development and its accuracy: a systematic review. Eur J Clin Pharmacol 74, 1365–1376 (2018). https://doi.org/10.1007/s00228-018-2513-6

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