Evidence map›Paper›PMID 42272844›Full record

ArticleFrontiers in pharmacology2026

Development of an adult whole-body PBPK model of irinotecan and its metabolites for predicting UGT1A1/CYP3A-mediated drug-drug interactions.

Bowen Chen, Longjie Li, Wenhang Xu, Haiping Xu, Xinyan Zhu, Qingfeng He, Xiao Zhu, Paul Chi-Lui Ho, Xiaoqiang Xiang, Peiying Ji

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Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

10 authors.

Bowen Chen *Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China.
Longjie Li *Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China.
Wenhang XuDepartment of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China.
Haiping XuDepartment of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China.
Xinyan ZhuDepartment of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China.
Qingfeng HeDepartment of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China.
Xiao ZhuDepartment of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China.
Paul Chi-Lui HoSchool of Pharmacy, Monash University Malaysia, Subang Jaya, Malaysia.
Xiaoqiang XiangDepartment of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China.
Peiying JiDepartment of Pharmacy, Kong Jiang Hospital of Yangpu District, Shanghai, China.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Background: Irinotecan (CPT-11) is a prodrug that is bioactivated to SN-38, which is primarily cleared via UGT1A1-mediated glucuronidation. Its complex metabolism, which also involves CYP3A-mediated oxidation, makes irinotecan highly susceptible to enzyme-mediated drug-drug interactions (DDIs). This study aimed to develop and qualify an adult whole-body physiologically based pharmacokinetic (PBPK) model of irinotecan and its metabolites (SN-38, SN-38G, and APC) to predict systemic pharmacokinetics and UGT1A1/CYP3A-mediated DDIs. Methods: An adult middle-out PBPK model was implemented in Simcyp®, integrating key pathways for carboxylesterase (CES) -mediated activation, UGT1A1/UGT1A9-driven glucuronidation, and CYP3A4/5-mediated oxidation. The model was calibrated using 175-300 mg/m Results: Most observed irinotecan and SN-38 concentrations fell within the fifth-95th percentile prediction intervals, and dose-exposure slopes were close to unity. Across monotherapy evaluations, 54/56 (96.4%) comparisons of maximum concentration (C Conclusion: The mechanistically informed and validated whole-body PBPK model reliably describes dose-dependent irinotecan and SN-38 pharmacokinetics and UGT1A1/CYP3A-mediated drug-drug interactions. This framework provides a clinically relevant tool for enzyme-mediated DDI risk assessment and for exploratory simulation of dose-exposure relationships under standard irinotecan regimens.

Indexed as

cyp3adrug-drug interactionsirinotecanphysiologically based pharmacokinetic modelSN-38UGT1A1

Identifiers

PMID42272844
PMCPMC13246723

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