Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, Richmond, VA, USA.
Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
Int J Pharm. 2024 Nov 15;665:124660. doi: 10.1016/j.ijpharm.2024.124660. Epub 2024 Sep 3.
The objectives of this study were to expand and implement a Computational Fluid Dynamics (CFD)-Dissolution, Absorption and Clearance (DAC)-Pharmacokinetics (PK) multi-physics modeling framework for simulating the transport of suspension-based nasal corticosteroid sprays. The mean CFD-predicted peak plasma concentration (C) and area under the curve (AUC) of the plasma concentration-time profile, based on three representative nasal airway models (capturing low, medium and high posterior spray deposition), were within one standard deviation of available in vivo PK data for a representative corticosteroid drug (triamcinolone acetonide). The relative differences in mean C between predictions and in vivo data for low dose (110 µg) and high dose (220 µg) cases were 27.8% and 10.1%, respectively. The models confirmed the dose-dependent dissolution-limited behavior of nasally delivered triamcinolone acetonide observed in available in vivo data. The total uptake from the nasal cavity decreased from 68.3% to 51.3% for the medium deposition model as dose was increased from 110 to 220 µg due to concentration-limited dissolution. The modeling framework is envisioned to facilitate faster development and testing of generic locally acting suspension nasal spray products due to its ability to predict the impact of differences in spray characteristics and patient use parameters on systemic PK.
本研究的目的是扩展和实施计算流体动力学（CFD）-溶解、吸收和清除（DAC）-药代动力学（PK）多物理建模框架，以模拟基于混悬剂的鼻用皮质类固醇喷雾的输送。基于三个代表性的鼻腔气道模型（捕捉低、中、高后喷雾沉积），CFD 预测的平均峰值血浆浓度 (C) 和血浆浓度-时间曲线下面积 (AUC) 与代表性皮质类固醇药物（曲安奈德）的可用体内 PK 数据在一个标准差内。低剂量（110μg）和高剂量（220μg）情况下，预测值与体内数据之间平均 C 的相对差异分别为 27.8%和 10.1%。模型证实了体内观察到的曲安奈德鼻内递送的溶解限制剂量依赖性。由于浓度限制溶解，从中鼻甲喷雾沉积模型中鼻腔的总吸收率从 68.3%下降到 51.3%，剂量从 110μg增加到 220μg。由于其能够预测喷雾特性和患者使用参数差异对全身 PK 的影响，该建模框架有望促进通用局部作用混悬鼻用喷雾产品的更快开发和测试。
