Defraeye Thijs, Bahrami Flora, Rossi René M
Empa, Swiss Federal Laboratories for Materials Science and Technology, Laboratory for Biomimetic Membranes and Textiles, St. Gallen, Switzerland.
University of Bern, ARTORG Center for Biomedical Engineering Research, Bern, Switzerland.
Front Pharmacol. 2021 Apr 29;12:641111. doi: 10.3389/fphar.2021.641111. eCollection 2021.
Transdermal drug delivery systems are a key technology to administer drugs with a high first-pass effect in a non-invasive and controlled way. Physics-based modeling and simulation are on their way to become a cornerstone in the engineering of these healthcare devices since it provides a unique complementarity to experimental data and additional insights. Simulations enable to virtually probe the drug transport inside the skin at each point in time and space. However, the tedious experimental or numerical determination of material properties currently forms a bottleneck in the modeling workflow. We show that multiparameter inverse modeling to determine the drug diffusion and partition coefficients is a fast and reliable alternative. We demonstrate this strategy for transdermal delivery of fentanyl. We found that inverse modeling reduced the normalized root mean square deviation of the measured drug uptake flux from 26 to 9%, when compared to the experimental measurement of all skin properties. We found that this improved agreement with experiments was only possible if the diffusion in the reservoir holding the drug was smaller than the experimentally measured diffusion coefficients suggested. For indirect inverse modeling, which systematically explores the entire parametric space, 30,000 simulations were required. By relying on direct inverse modeling, we reduced the number of simulations to be performed to only 300, so a factor 100 difference. The modeling approach's added value is that it can be calibrated once in-silico for all model parameters simultaneously by solely relying on a single measurement of the drug uptake flux evolution over time. We showed that this calibrated model could accurately be used to simulate transdermal patches with other drug doses. We showed that inverse modeling is a fast way to build up an accurate mechanistic model for drug delivery. This strategy opens the door to clinically ready therapy that is tailored to patients.
经皮给药系统是一种以非侵入性和可控方式给药具有高首过效应药物的关键技术。基于物理的建模和模拟正逐渐成为这些医疗设备工程中的基石，因为它为实验数据提供了独特的互补性并带来额外的见解。模拟能够在每个时间和空间点虚拟探测皮肤内的药物传输。然而，目前材料特性繁琐的实验或数值确定在建模工作流程中形成了一个瓶颈。我们表明，用于确定药物扩散和分配系数的多参数逆建模是一种快速且可靠的替代方法。我们展示了这种用于芬太尼经皮给药的策略。我们发现，与对所有皮肤特性进行实验测量相比，逆建模将测量的药物摄取通量的归一化均方根偏差从26%降低到了9%。我们发现，只有当容纳药物的储库中的扩散小于实验测量的扩散系数时，才有可能与实验取得更好的一致性。对于系统探索整个参数空间的间接逆建模，需要进行30000次模拟。通过依靠直接逆建模，我们将需要执行的模拟次数减少到仅300次，相差100倍。该建模方法的附加值在于，仅依靠对药物摄取通量随时间演变的单次测量，就可以在计算机上一次性同时校准所有模型参数。我们表明，这种校准后的模型可准确用于模拟其他药物剂量的经皮贴剂。我们表明，逆建模是建立准确的药物递送机理模型的快速方法。这种策略为针对患者量身定制的临床可用疗法打开了大门。
