Modeling Pharmacokinetics in Steatotic Livers (SteaPKMod)

脂肪肝中的药代动力学建模 (SteaPKMod)

• 批准号: 410848700
• 负责人: Professorin Dr. Uta Dahmen
• 金额: --
• 依托单位: Fraunhofer-Institut für Digitale Medizin (MEVIS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410848700?language=en
• 关键词: Modeling; Pharmacokinetics; Steatotic; Livers; SteaPKMod

*Challenge* Liver diseases lead to impairment of drug metabolism, making appropriate drug dosing difficult. Cellular metabolic capability and disease manifestation are subject to a spatially heterogeneous distribution at different physiologically relevant spatial scales: inhomogeneous across the entire organ, but also zonated within liver lobules, the smallest hepatic functional units. Drug metabolism can be expected to be most affected if diseased and metabolically active regions coincide.Current pharmacokinetics (PK) models take into account liver diseases in cumulative form, without representing the relevant spatial heterogeneity of disease-related local changes of metabolic capability. They hence lack indispensable capabilities for investigating the interplay between different patterns of heterogeneity and for predicting the specific impact of, e.g., zonated diseases or surgery on the overall metabolic capability.*Goal* We will develop a mathematical PK~model for individualized dosage optimization and diagnosis support in zonated and heterogeneously distributed liver diseases such as steatosis.This novel model will consider the interplay of spatially inhomogeneous metabolic capabilities and diseased states of cells and thus permit in silico investigations with unprecedented accuracy. Moreover, it will be the foundation for future clinical applications of decision support and risk assessment, e.g., by predicting remnant metabolic capacity after liver resections.*Approach* As showcases, we will investigate two example drugs representing classes of clinically relevant drugs metabolized by different cytochrome P450 enzymes (CYPs). PK~data will be obtained in normal mice and mice with alcoholic or non-alcoholic steatosis, two frequent and well-characterized liver diseases with distinct zonation patterns of lipid accumulations. Based on our feasibility study [DOI 10.1016/j.compbiomed.2016.04.004], we will quantify zonation and heterogeneity of steatotic lipid accumulations and the presence of enzymes.For the mathematical model using ordinary and partial differential equations, we will develop a novel mechanistic representation of how steatosis affects the hepatic cellular drug metabolism, e.g., via altered cellular properties, sinusoidal morphology, or hemodynamics at the relevant spatial scales. Tailored to the spatial multiscale structure of the model, we will implement drug-specific PK models. After successful validation of model predictions, we will apply the simulations for dosage optimization and for diagnosis support by deducing the underlying zonal alteration from changes in drug metabolism.With this preclinical proof of principle we will show that the approach is applicable for individualized therapy planning.

*挑战*肝病导致药物代谢障碍，使适当的药物剂量变得困难。细胞代谢能力和疾病表现受制于不同生理相关空间尺度上的空间异质性分布：在整个器官中不均匀，但也在最小的肝脏功能单位--肝小叶内呈带状分布。如果疾病和代谢活性区域重合，药物代谢可能会受到最大的影响。目前的药代动力学(PK)模型以累积的形式考虑了肝脏疾病，而没有代表与疾病相关的局部代谢能力变化的相关空间异质性。因此，他们缺乏必要的能力来研究不同异质性模式之间的相互作用，并预测例如分区疾病或手术对整体代谢能力的具体影响。*目标*我们将开发一个数学PK~模型，用于分区和异质分布的肝病(如脂肪肝)的个体化剂量优化和诊断支持。这个新的模型将考虑空间不均匀的代谢能力和细胞疾病状态的相互作用，从而允许以前所未有的精度进行计算机研究。此外，这将是未来决策支持和风险评估的基础，例如通过预测肝切除后的剩余代谢能力。*方法*作为展示案例，我们将研究两种代表不同细胞色素P450酶(Cyps)代谢的临床相关药物类别的示例药物。PK~数据将在正常小鼠和酒精性或非酒精性脂肪变性小鼠中获得，这两种常见且特征良好的肝病具有不同的脂肪堆积带状模式。基于我们的可行性研究[DOI 10.1016/j.combied.2016.04.004]，我们将量化脂肪变性脂肪堆积的地带性和异质性以及酶的存在。对于使用常微分方程和偏微分方程的数学模型，我们将在相关的空间尺度上建立脂肪变性如何影响肝细胞药物代谢的新的机制表示，例如，通过改变细胞特性、正弦形态或血流动力学。针对模型的空间多尺度结构，我们将实现药物特异性PK模型。在成功验证模型预测后，我们将通过从药物代谢的变化中推断潜在的区带变化，将模拟应用于剂量优化和诊断支持。通过这种临床前原则证明，我们将证明该方法适用于个性化治疗计划。