*Result*: Utility of Modeling and Simulations in Drug Development: Contrasting Japan, US and UK Descriptions of PBPK Modeling from Package Inserts.
Title:
Utility of Modeling and Simulations in Drug Development: Contrasting Japan, US and UK Descriptions of PBPK Modeling from Package Inserts.
Authors:
Kudo S; Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan., Wakuda H; Clinical Pharmacology Center, Oita University Hospital, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan. wakuda@oita-u.ac.jp., Oikawa I; General Clinical Research Center, Oita University Hospital, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan., Sekiguchi A; Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan., Nakamura Y; Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan., Hojo T; Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan., Imai H; Department of Medical Ethics, Faculty of Medicine, Oita University, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan., Kai M; Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan., Uemura N; Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan.; Clinical Pharmacology Center, Oita University Hospital, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan.; General Clinical Research Center, Oita University Hospital, 1-1 Idai Gaoka, Hasama-Cho, Yufu City, Oita, 879-5593, Japan.
Source:
The AAPS journal [AAPS J] 2026 Feb 10; Vol. 28 (2), pp. 60. Date of Electronic Publication: 2026 Feb 10.
Publication Type:
Journal Article; Comparative Study
Language:
English
Journal Info:
Publisher: American Association of Pharmaceutical Scientists Country of Publication: United States NLM ID: 101223209 Publication Model: Electronic Cited Medium: Internet ISSN: 1550-7416 (Electronic) Linking ISSN: 15507416 NLM ISO Abbreviation: AAPS J Subsets: MEDLINE
Imprint Name(s):
Original Publication: Arlington, Va., USA : American Association of Pharmaceutical Scientists, [2004]-
MeSH Terms:
References:
Emoto C, Doki K, Matsumoto Y, et al. Applications of PBPK modeling and simulations in the clinical pharmacology field: lessons from several case studies. Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics. 2020;51(6):331–44. (PMID: 10.3999/jscpt.51.331)
Jones HM, Rowland-Yeo K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT Pharmacometrics Syst Pharmacol. 2013;2:e63. https://doi.org/10.1038/psp.2013.41 . (PMID: 10.1038/psp.2013.41239456043828005)
Rowland M, Peck CC, Tucker GT. Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol. 2011;51:45–73. https://doi.org/10.1146/annurev-pharmtox-010510-100540 . (PMID: 10.1146/annurev-pharmtox-010510-10054020854171)
Rostami-Hodjegan A. Physiologically based pharmacokinetics joined with in vitro–in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology. Clin Pharmacol Ther. 2012;92(1):50–61. (PMID: 10.1038/clpt.2012.6522644330)
Demeester C, Robins D, Edwina AE, et al. Physiologically based pharmacokinetic (PBPK) modelling of oral drug absorption in older adults – an AGePOP review. Eur J Pharm Sci. 2023;188:106496. https://doi.org/10.1016/j.ejps.2023.106496 . (PMID: 10.1016/j.ejps.2023.10649637329924)
Kijima S, Yoshida S, Ochiai Y. Activity and perspective on quantitative modeling and simulation in Japan: update from PMDA. CPT Pharmacometrics Syst Pharmacol. 2022;11:1552–5. https://doi.org/10.1002/psp4.12868 . (PMID: 10.1002/psp4.12868361991979755913)
Jamei M. Recent advances in development and application of physiologically based pharmacokinetic (PBPK) models: a transition from academic curiosity to regulatory acceptance. Curr Pharmacol Rep. 2016;2(4):161–9. https://doi.org/10.1007/s40495-016-0059-9 . (PMID: 10.1007/s40495-016-0059-9272269534856711)
Hasegawa M, Kijima S. MIDD in Japan – implementations, challenges and opportunities. Adv Drug Deliv Rev. 2025;220:115553. https://doi.org/10.1016/j.addr.2025.115553 . (PMID: 10.1016/j.addr.2025.11555340024482)
US Food and Drug Administration. Physiologically based pharmacokinetic analyses — format and content: guidance for industry. FDA. 2018. Available from https://www.fda.gov/media/101469/download . Accessed 16 July 2024.
European Medicines Agency. Guideline on the reporting of Physiologically Based Pharmacokinetic (PBPK) modelling and simulation. EMA. 2018. Available from https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation_en.pdf . Accessed 19 Nov 2024.
Shebley M, Sandhu P, Emami Riedmaier A, Jamei M, Narayanan R, Patel A, et al. Physiologically based pharmacokinetic model qualification and reporting procedures for regulatory submissions: a consortium perspective. Clin Pharmacol Ther. 2018;104(1):88–110. https://doi.org/10.1002/cpt.1013. (PMID: 10.1002/cpt.1013.293155046032820)
Paul P, Colin PJ, Musuamba Tshinanu F, Versantvoort C, Manolis E, Blake K. Current use of physiologically based pharmacokinetic modeling in new medicinal product approvals at EMA. Clin Pharmacol Ther. 2025;117(3):808–17. https://doi.org/10.1002/cpt.3525 . (PMID: 10.1002/cpt.35253974853811835421)
Li Y, Sun H, Zhang Z. The evolution and future directions of PBPK modeling in FDA regulatory review. Pharmaceutics. 2025;17(11):1413. https://doi.org/10.3390/pharmaceutics17111413 . (PMID: 10.3390/pharmaceutics171114134130475112655628)
Sun Z, Zhao N, Zhao X, Wang Z, Liu Z, Cui Y. Application of physiologically based pharmacokinetic modeling of novel drugs approved by the U.S. food and drug administration. Eur J Pharm Sci. 2024;200:106838. https://doi.org/10.1016/j.ejps.2024.106838 . (PMID: 10.1016/j.ejps.2024.10683838960205)
Johnson TN, Small BG, Berglund EG, Rowland Yeo K. A best practice framework for applying physiologically based pharmacokinetic modeling to pediatric drug development. CPT: Pharmacometrics & Systems Pharmacology. 2021;10(9):967–72. https://doi.org/10.1002/psp4.12678 . (PMID: 10.1002/psp4.12678)
Johnson TN, Small BG, Rowland Yeo K. Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations. CPT: Pharmacometrics & Systems Pharmacology. 2022;11:373–83. https://doi.org/10.1002/psp4.12764 . (PMID: 10.1002/psp4.12764)
Edginton AN, Schmitt W, Voith B, Willmann S. Physiologically-based pharmacokinetic models for children: lessons learned and future perspectives. Expert Opin Drug Metab Toxicol. 2006;2(6):965–73. https://doi.org/10.1517/17425255.2.6.965 . (PMID: 10.1517/17425255.2.6.965)
Shebley M, Sandhu P, Emami Riedmaier A, et al. Physiologically based pharmacokinetic model qualification and reporting procedures for regulatory submissions: a consortium perspective. Clin Pharmacol Ther. 2018;104(5):865–79. https://doi.org/10.1002/cpt.1013 . (PMID: 10.1002/cpt.1013)
Kuemmel C, Yang Y, Zhang X, et al. Consideration of a credibility assessment framework in model-informed drug development: potential application to physiologically based pharmacokinetic modeling and simulation. CPT: Pharmacometrics & Systems Pharmacology. 2020;9(1):21–8. https://doi.org/10.1002/psp4.12479 . (PMID: 10.1002/psp4.12479)
Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: a systematic review of published models, applications, and model verification. Drug Metab Dispos. 2015;43(10):1823–37. https://doi.org/10.1124/dmd.115.064571 . (PMID: 10.1124/dmd.115.064571262967094613950)
Chou P, Shannar A, Pan Y, Dave PD, Xu J, Kong A-NT. Application of physiologically-based pharmacokinetic (PBPK) model in drug development and in dietary phytochemicals. Curr Pharmacol Rep. 2025;11:45. https://doi.org/10.1007/s40495-025-00427-w . (PMID: 10.1007/s40495-025-00427-w4078698412334468)
Cheng YH, Thomas S, Tsang YC, Almeida S, Ashraf M, Fotaki N, et al. Advances in physiologically based pharmacokinetic (PBPK) modeling and its regulatory utility to support oral drug product development and harmonization. Pharm Res. 2025;42:819–33. https://doi.org/10.1007/s11095-025-03849-9 . (PMID: 10.1007/s11095-025-03849-94015550012158835)
Chou WC, Lin Z. Machine learning and artificial intelligence in physiologically based pharmacokinetic modeling. Toxicol Sci. 2023;191(1):1–14. https://doi.org/10.1093/toxsci/kfac101 . (PMID: 10.1093/toxsci/kfac101361561569887681)
Talkington AM, Cao Y, Kearsley AJ, Lai SK. Opportunities for machine learning and artificial intelligence in physiologically-based pharmacokinetic (PBPK) modeling. Adv Drug Deliv Rev. 2025;227:115716. https://doi.org/10.1016/j.addr.2025.115716 . (PMID: 10.1016/j.addr.2025.1157164109324012573771)
Arora S, Pepin X, Jamei M, Sharma P, Heimbach T, Wagner C, et al. Development of a physiologically based biopharmaceutics model report template: considerations for improved quality in view of regulatory submissions. Mol Pharm. 2025;22(6):2735–46. https://doi.org/10.1021/acs.molpharmaceut.5c00225 . (PMID: 10.1021/acs.molpharmaceut.5c002254030006412135060)
Mackie C, Arora S, Seo P, Moody R, Rege B, Pepin X, et al. Physiologically based biopharmaceutics modeling (PBBM): best practices for drug product quality, regulatory and industry perspectives: 2023 workshop summary report. Mol Pharm. 2024;21(5):2065–80. https://doi.org/10.1021/acs.molpharmaceut.4c00202 . (PMID: 10.1021/acs.molpharmaceut.4c002023860080411080464)
Heimbach T, Musuamba Tshinanu F, Raines K, Borges L, Kijima S, Malamatari M, et al. PBBM considerations for base models, model validation, and application steps: workshop summary report. Mol Pharm. 2024;21(11):5353–72. https://doi.org/10.1021/acs.molpharmaceut.4c00758 . (PMID: 10.1021/acs.molpharmaceut.4c007583934850811539057)
Jones HM, Rowland-Yeo K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT Pharmacometrics Syst Pharmacol. 2013;2:e63. https://doi.org/10.1038/psp.2013.41 . (PMID: 10.1038/psp.2013.41239456043828005)
Rowland M, Peck CC, Tucker GT. Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol. 2011;51:45–73. https://doi.org/10.1146/annurev-pharmtox-010510-100540 . (PMID: 10.1146/annurev-pharmtox-010510-10054020854171)
Rostami-Hodjegan A. Physiologically based pharmacokinetics joined with in vitro–in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology. Clin Pharmacol Ther. 2012;92(1):50–61. (PMID: 10.1038/clpt.2012.6522644330)
Demeester C, Robins D, Edwina AE, et al. Physiologically based pharmacokinetic (PBPK) modelling of oral drug absorption in older adults – an AGePOP review. Eur J Pharm Sci. 2023;188:106496. https://doi.org/10.1016/j.ejps.2023.106496 . (PMID: 10.1016/j.ejps.2023.10649637329924)
Kijima S, Yoshida S, Ochiai Y. Activity and perspective on quantitative modeling and simulation in Japan: update from PMDA. CPT Pharmacometrics Syst Pharmacol. 2022;11:1552–5. https://doi.org/10.1002/psp4.12868 . (PMID: 10.1002/psp4.12868361991979755913)
Jamei M. Recent advances in development and application of physiologically based pharmacokinetic (PBPK) models: a transition from academic curiosity to regulatory acceptance. Curr Pharmacol Rep. 2016;2(4):161–9. https://doi.org/10.1007/s40495-016-0059-9 . (PMID: 10.1007/s40495-016-0059-9272269534856711)
Hasegawa M, Kijima S. MIDD in Japan – implementations, challenges and opportunities. Adv Drug Deliv Rev. 2025;220:115553. https://doi.org/10.1016/j.addr.2025.115553 . (PMID: 10.1016/j.addr.2025.11555340024482)
US Food and Drug Administration. Physiologically based pharmacokinetic analyses — format and content: guidance for industry. FDA. 2018. Available from https://www.fda.gov/media/101469/download . Accessed 16 July 2024.
European Medicines Agency. Guideline on the reporting of Physiologically Based Pharmacokinetic (PBPK) modelling and simulation. EMA. 2018. Available from https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation_en.pdf . Accessed 19 Nov 2024.
Shebley M, Sandhu P, Emami Riedmaier A, Jamei M, Narayanan R, Patel A, et al. Physiologically based pharmacokinetic model qualification and reporting procedures for regulatory submissions: a consortium perspective. Clin Pharmacol Ther. 2018;104(1):88–110. https://doi.org/10.1002/cpt.1013. (PMID: 10.1002/cpt.1013.293155046032820)
Paul P, Colin PJ, Musuamba Tshinanu F, Versantvoort C, Manolis E, Blake K. Current use of physiologically based pharmacokinetic modeling in new medicinal product approvals at EMA. Clin Pharmacol Ther. 2025;117(3):808–17. https://doi.org/10.1002/cpt.3525 . (PMID: 10.1002/cpt.35253974853811835421)
Li Y, Sun H, Zhang Z. The evolution and future directions of PBPK modeling in FDA regulatory review. Pharmaceutics. 2025;17(11):1413. https://doi.org/10.3390/pharmaceutics17111413 . (PMID: 10.3390/pharmaceutics171114134130475112655628)
Sun Z, Zhao N, Zhao X, Wang Z, Liu Z, Cui Y. Application of physiologically based pharmacokinetic modeling of novel drugs approved by the U.S. food and drug administration. Eur J Pharm Sci. 2024;200:106838. https://doi.org/10.1016/j.ejps.2024.106838 . (PMID: 10.1016/j.ejps.2024.10683838960205)
Johnson TN, Small BG, Berglund EG, Rowland Yeo K. A best practice framework for applying physiologically based pharmacokinetic modeling to pediatric drug development. CPT: Pharmacometrics & Systems Pharmacology. 2021;10(9):967–72. https://doi.org/10.1002/psp4.12678 . (PMID: 10.1002/psp4.12678)
Johnson TN, Small BG, Rowland Yeo K. Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations. CPT: Pharmacometrics & Systems Pharmacology. 2022;11:373–83. https://doi.org/10.1002/psp4.12764 . (PMID: 10.1002/psp4.12764)
Edginton AN, Schmitt W, Voith B, Willmann S. Physiologically-based pharmacokinetic models for children: lessons learned and future perspectives. Expert Opin Drug Metab Toxicol. 2006;2(6):965–73. https://doi.org/10.1517/17425255.2.6.965 . (PMID: 10.1517/17425255.2.6.965)
Shebley M, Sandhu P, Emami Riedmaier A, et al. Physiologically based pharmacokinetic model qualification and reporting procedures for regulatory submissions: a consortium perspective. Clin Pharmacol Ther. 2018;104(5):865–79. https://doi.org/10.1002/cpt.1013 . (PMID: 10.1002/cpt.1013)
Kuemmel C, Yang Y, Zhang X, et al. Consideration of a credibility assessment framework in model-informed drug development: potential application to physiologically based pharmacokinetic modeling and simulation. CPT: Pharmacometrics & Systems Pharmacology. 2020;9(1):21–8. https://doi.org/10.1002/psp4.12479 . (PMID: 10.1002/psp4.12479)
Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N. Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: a systematic review of published models, applications, and model verification. Drug Metab Dispos. 2015;43(10):1823–37. https://doi.org/10.1124/dmd.115.064571 . (PMID: 10.1124/dmd.115.064571262967094613950)
Chou P, Shannar A, Pan Y, Dave PD, Xu J, Kong A-NT. Application of physiologically-based pharmacokinetic (PBPK) model in drug development and in dietary phytochemicals. Curr Pharmacol Rep. 2025;11:45. https://doi.org/10.1007/s40495-025-00427-w . (PMID: 10.1007/s40495-025-00427-w4078698412334468)
Cheng YH, Thomas S, Tsang YC, Almeida S, Ashraf M, Fotaki N, et al. Advances in physiologically based pharmacokinetic (PBPK) modeling and its regulatory utility to support oral drug product development and harmonization. Pharm Res. 2025;42:819–33. https://doi.org/10.1007/s11095-025-03849-9 . (PMID: 10.1007/s11095-025-03849-94015550012158835)
Chou WC, Lin Z. Machine learning and artificial intelligence in physiologically based pharmacokinetic modeling. Toxicol Sci. 2023;191(1):1–14. https://doi.org/10.1093/toxsci/kfac101 . (PMID: 10.1093/toxsci/kfac101361561569887681)
Talkington AM, Cao Y, Kearsley AJ, Lai SK. Opportunities for machine learning and artificial intelligence in physiologically-based pharmacokinetic (PBPK) modeling. Adv Drug Deliv Rev. 2025;227:115716. https://doi.org/10.1016/j.addr.2025.115716 . (PMID: 10.1016/j.addr.2025.1157164109324012573771)
Arora S, Pepin X, Jamei M, Sharma P, Heimbach T, Wagner C, et al. Development of a physiologically based biopharmaceutics model report template: considerations for improved quality in view of regulatory submissions. Mol Pharm. 2025;22(6):2735–46. https://doi.org/10.1021/acs.molpharmaceut.5c00225 . (PMID: 10.1021/acs.molpharmaceut.5c002254030006412135060)
Mackie C, Arora S, Seo P, Moody R, Rege B, Pepin X, et al. Physiologically based biopharmaceutics modeling (PBBM): best practices for drug product quality, regulatory and industry perspectives: 2023 workshop summary report. Mol Pharm. 2024;21(5):2065–80. https://doi.org/10.1021/acs.molpharmaceut.4c00202 . (PMID: 10.1021/acs.molpharmaceut.4c002023860080411080464)
Heimbach T, Musuamba Tshinanu F, Raines K, Borges L, Kijima S, Malamatari M, et al. PBBM considerations for base models, model validation, and application steps: workshop summary report. Mol Pharm. 2024;21(11):5353–72. https://doi.org/10.1021/acs.molpharmaceut.4c00758 . (PMID: 10.1021/acs.molpharmaceut.4c007583934850811539057)
Contributed Indexing:
Keywords: drug Development; modeling and Simulation (M&S); package Inserts; physiologically-based Pharmacokinetic (PBPK)
Entry Date(s):
Date Created: 20260210 Date Completed: 20260210 Latest Revision: 20260210
Update Code:
20260211
DOI:
10.1208/s12248-026-01211-4
PMID:
41667884
Database:
MEDLINE
*Further Information*
*Physiologically based pharmacokinetic (PBPK) modeling is a mathematical method for predicting drug pharmacokinetics based on individual physiological information, and its usefulness has been attracting attention in recent years. This study aimed to investigate and compare the extent to which PBPK models are utilized in drug package inserts in Japan, the United States, and Europe. We searched the official websites of the PMDA, FDA, and EMA to examine the number and content of drugs that mention the use of PBPK modeling as of 2024. Furthermore, we compared the consistency and detail of the descriptions between Japan, the United States, and Europe. As a result, 38 drugs in Japan listed PBPK modeling, many of which were related to drug-drug interactions. Compared with Europe, there were no complete matches and only seven partial matches, while compared with the United States, there were two complete matches and 24 partial matches. A comparison of the details of the 24 partial matches revealed a tendency for Japanese package inserts to be more detailed. PBPK model analysis has become increasingly important in recent drug development, and Japan in particular has a tendency to provide more detailed information on package inserts. This study suggests the potential for further utilization of PBPK models in the field of clinical pharmacology.
(© 2026. The Author(s).)*
*Declarations. Conflict of Interest: All authors declare no conflicts of interest.*