Computational Model of In Vivo Corneal Pharmacokinetics and Pharmacodynamics of Topically Administered Ophthalmic Drug Products.
Computational Model of In Vivo Corneal Pharmacokinetics and Pharmacodynamics of Topically Administered Ophthalmic Drug Products.
复制标题
局部给药眼科药品的体内角膜药代动力学和药效学的计算模型。
DOI：
10.1007/s11095-023-03480-6
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发表时间：
2023
影响因子：
3.7
通讯作者：
Tan,Ming-Liang
中科院分区：
文献类型：
--
作者：
German,Carrie;Chen,Zhijian;Przekwas,Andrzej;Walenga,Ross;Babiskin,Andrew;Zhao,Liang;Fan,Jianghong;Tan,Ming-Liang
虽然眼睛可以直接接触到人体表面，但由于眼部组织中存在多重保护屏障，药物递送可能极具挑战性。研究人员已经开发出复杂的配方策略来克服眼科药物输送的这些障碍。目前的发展策略严重依赖于体外实验和动物试验来预测人体药代动力学（PK）和药效学（PD）。目的建立一种高保真的眼前PK/PD模型，用于眼科药物的局部应用。方法在此，我们提出了一种基于生理学的计算机方法来预测兔外用眼科产品后的PK和PD。基于第一线原理的方法被用来描述噻洛尔的溶解，运输和分布，包括考虑电离运输，局部滴注噻洛尔悬浮液。结果利用文献传递和反应参数，计算模型较好地描述了家兔的浓度-时间和反应-时间曲线。经过验证的兔模型结果与外推的人体模型结果的比较表明，在多个时间点上噻莫洛尔的分布存在明显差异。结论该模型框架为基于模型预测眼部局部用药后眼组织PK和PD的变化提供了工具。
IntroductionAlthough the eye is directly accessible on the surface of the human body, drug delivery can be extremely challenging due to the presence of multiple protective barriers in eye tissues. Researchers have developed complex formulation strategies to overcome these barriers to ophthalmic drug delivery. Current development strategies rely heavily onin vitroexperiments and animal testing to predict human pharmacokinetics (PK) and pharmacodynamics (PD).ObjectiveThe primary objective of the study was to develop a high-fidelity PK/PD model of the anterior eye for topical application of ophthalmic drug products.MethodsHere, we present a physiologically-based in silico approach to predicting PK and PD in rabbits after topical administration of ophthalmic products. A first-principles based approach was used to describe timolol dissolution, transport, and distribution, including consideration of ionized transport, following topical instillation of a timolol suspension.ResultsUsing literature transport and response parameters, the computational model described well the concentration–time and response-time profiles in rabbit. Comparison of validated rabbit model results and extrapolated human model results demonstrate observable differences in the distribution of timolol at multiple time points.ConclusionThis modeling framework provides a tool for model-based prediction of PK in eye tissues and PD after topical ophthalmic drug administration to the eyes.