Zheng Aole, Han Tian, Bu Fengjiao, He Qingfeng, Shang Jianmin, Ho Paul Chi Lui, Xiang Xiaoqiang, Zhou Xingtao, Huang Taomin
Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, 201203, China.
Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China.
AAPS J. 2025 May 2;27(4):89. doi: 10.1208/s12248-025-01052-7.
Developing a mathematical model to predict the distribution and bioavailability of atropine in human eyes is an insight approach for clinical practice. This study aims to develop a human ocular physiologically based pharmacokinetic (PBPK) modeling for the ophthalmic drug atropine and explore possible mechanisms by which atropine reduces myopia progression in children. The Ocular Compartment Absorption and Transit (OCAT™) model was employed to describe the ocular distribution of atropine following administration at different dosages in both rabbits and humans. The PBPK model enables the extrapolation of pharmacokinetic characteristics among different species depending on theirphysiology and anatomy. The developed and validated OCAT-PBPK model demonstrated good agreement with observed data from rabbit ocular tissues and human aqueous humor. Fifty-eight percent of simulations fell within the standard deviation range of experimental data. The extrapolated human PBPK model for accurately predicted the ocular exposure and distribution following the administration of low-concentration atropine. This study confirms the performance of the ocular PBPK model in predicting ocular pharmacokinetic behavior among different species. Model's predictions indicate that atropine shows significant potential to penetrate the posterior eye segment, providing underlying insights into its mechanisms of action in the eye.
建立一个数学模型来预测阿托品在人眼中的分布和生物利用度是一种对临床实践有深刻见解的方法。本研究旨在建立一种基于人体眼部生理的药代动力学（PBPK）模型，用于眼科药物阿托品，并探索阿托品减缓儿童近视进展的可能机制。采用眼室吸收和转运（OCAT™）模型来描述不同剂量给药后阿托品在兔和人眼中的分布。PBPK模型能够根据不同物种的生理和解剖结构推断其药代动力学特征。所建立并验证的OCAT-PBPK模型与兔眼组织和人房水的观察数据显示出良好的一致性。58%的模拟结果落在实验数据的标准差范围内。外推得到的人体PBPK模型准确预测了低浓度阿托品给药后的眼部暴露和分布情况。本研究证实了眼部PBPK模型在预测不同物种眼部药代动力学行为方面的性能。模型预测表明，阿托品具有穿透眼后节的显著潜力，为其在眼部的作用机制提供了潜在的见解。
