Speaker
Description
Authors:
Longjie Li (1)†, Mengfan Ye (2) (3)†, Wenhang Xu (1), Xinyan Zhu (1), Haiping Xu (1), Qingfeng He (1), Xiao Zhu (1), Juan Xie (2) (3), Xiaoqiang Xiang (1)
Affiliations:
(1) Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China
(2) Department of General Medicine at Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
(3) Center of Community-Based Health Research, Fudan University, Shanghai, China
*Correspondence: Juan Xie (abclux@126.com); Xiaoqiang Xiang(xiangxq@fudan.edu.cn)
† Longjie Li and Mengfan Ye contributed equally to this work.
Abstract:
Background: Hepatic organic anion transporting polypeptide 1B1 (OATP1B1) is a key determinant of drug disposition. Coproporphyrin I (CPI), an endogenous substrate predominantly cleared via OATP1B1, is used to assess OATP1B1-mediated DDIs; however, serum CPI concentrations in Chinese adults have not been reported.
Methods: Serum CPI was quantified in 128 Chinese inpatients by UHPLC–MS/MS and analyzed by age, sex, and frailty. A Chinese whole-body physiologically based pharmacokinetic (PBPK) model was developed and evaluated against published Caucasian, Indian, and Japanese datasets, with cross-population adaptation mainly via CPI synthesis rate. A rifampicin–CPI module assessed DDI predictability, and PBPK analyses explored mechanisms of frailty-associated CPI changes.
Results: CPI was higher in patients aged ≥60 versus <60 years and further increased in frail versus non-frail individuals within the ≥60-year group; males had higher CPI than females. The model reproduced CPI across Chinese subgroups (fold-error 0.8–1.2) and across Caucasian, Indian, and Japanese datasets (within 1.5-fold). The rifampicin–CPI DDI was predicted within a two-fold range for Cmax and AUC0–t ratios. Mechanistic analyses suggested that elevated CPI in frail Chinese older adults is consistent with an approximately 41% reduction in hepatic OATP1B1 functional abundance versus non-frail older adults, reducing clearance and causing CPI accumulation.
Conclusions: This work establishes the first quantitative description of CPI disposition in Chinese adults and an externally qualified CPI-PBPK framework to interpret CPI as an endogenous OATP1B1 biomarker. The framework supports individualized dosing and safety management for OATP1B1 substrates in older and frail populations.
Acknowledgements:
This scientific research was funded by Shanghai Fifth People’s Hospital, Fudan University (No. 2023WYRH10)
