Research Department, CFD Research Corporation, Huntsville, Alabama.
Int J Numer Method Biomed Eng. 2020 Mar;36(3):e3317. doi: 10.1002/cnm.3317. Epub 2020 Feb 9.
Most Food and Drug Administration (FDA)-approved drugs are administered orally, despite the complex process of oral drug absorption that is difficult to analyze experimentally. Oral bioavailability is dependent on the drug compound as well as the physiological and anatomical states of the user. Thus, computational models have emerged to mechanistically capture and predict the oral absorption process. The current models are generally 0D compartmental models and are limited by (a) simplified physiological characteristics of the gastrointestinal tract (GIT), (b) semiempirical/analytical dissolution profiles of the tested drugs, (c) incorrect absorption for some drug BCS classes (class IIa, for example), (d) GITs size variability among population, (e) incorrectly predicting the absorption of drugs that are GIT target specific, and (f) erroneous mixing in the domain. In this study, we have developed a multiscale absorption and transit (MAT) toolkit to simulate the dissolution, transport, absorption, distribution, metabolism, and elimination of orally administered drugs in the human GIT at multiple levels. MAT was constructed by integrating the spatially accurate first-principles driven high-fidelity drug transport, dissolution, and absorption model in the human stomach and GIT using our recently published quasi-3D (Q3D) framework. The process integrated the multilayer intestine physiologically based pharmacokinetics models with the whole-body compartmental models to predict the systemic pharmacokinetics of oral drugs. The computational results showed that this multiscale tool was able to match the experimental concentration results (individual and population) better than the traditional compartmental models. Ultimately, MAT will be developed into a commercial product to meet urgent demands from pharmaceutical and biomedical industries.
大多数经美国食品和药物管理局 (FDA) 批准的药物都是口服给药，尽管口服药物吸收的过程非常复杂，难以进行实验分析。口服生物利用度取决于药物化合物以及使用者的生理和解剖状态。因此，已经出现了计算模型来从机制上捕捉和预测口服吸收过程。目前的模型通常是 0D 隔室模型，受到以下因素的限制：(a) 胃肠道 (GIT) 的简化生理特征；(b) 测试药物的半经验/分析溶解曲线；(c) 某些药物 BCS 类别（例如 IIa 类）的吸收不正确；(d) 人群中 GIT 大小的可变性；(e) 错误预测针对 GIT 的特定药物的吸收；(f) 域内错误混合。在这项研究中，我们开发了一个多尺度吸收和转运 (MAT) 工具包，以在多个层面模拟口服药物在人体 GIT 中的溶解、转运、吸收、分布、代谢和消除。MAT 通过使用我们最近发表的准 3D (Q3D) 框架在人体胃和 GIT 中集成具有空间准确性的基于原理的高保真药物转运、溶解和吸收模型来构建。该过程将多层肠生理药代动力学模型与全身隔室模型集成在一起，以预测口服药物的全身药代动力学。计算结果表明，与传统隔室模型相比，这种多尺度工具能够更好地匹配实验浓度结果（个体和群体）。最终，MAT 将被开发为一种商业产品，以满足制药和生物医学行业的迫切需求。
