Abstract：
Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl\'s transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes an in-silico skin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3 % higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18 % lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8 % from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5 % and 33.3 %, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy outcome variability. This holds promise as a potentially useful tool for physicians.
摘要：
经皮给药适用于具有特异性亲脂性的低分子量药物，比如芬太尼,广泛用于癌症引起的疼痛管理。然而,芬太尼的透皮疗法显示出高的个体差异。诸如应用部位处的皮肤特征和环境温度的因素促成了这种变化。在这项研究中,我们开发了一种基于物理的人体数字孪生体，以应对这种可变性，并提出了更好的适应性设置。这对双胞胎包括一个用于药物渗透的电脑皮肤模型，药代动力学模型，和药效学模型。根据我们的模拟结果,在侧腹(侧腹部区域)应用贴剂显示血浆中芬太尼的最大浓度比胸部高15.3%。此外,通过侧翼输送时达到此最大浓度的时间为19.8小时，比上臂早10.3小时。最后,这种变化导致通过侧腹分娩的最小疼痛强度比胸部低18%.此外，通过考虑活动水平，研究了季节变化对环境温度和皮肤温度的影响。根据我们的结果,从冬季的非活动状态到夏季的活动状态，毛细血管的芬太尼吸收通量增加了11.8％。我们还通过调节贴剂的温度以减轻疼痛以达到轻度疼痛强度(在VAS量表上评级为3)来评估控制芬太尼递送的效果。通过实施这一战略，平均疼痛强度下降1.1分，血浆中芬太尼浓度和平均疼痛强度的标准偏差分别降低了37.5％和33.3％，分别。因此,我们的数字孪生证明了通过温度调节控制药物释放的功效，确保治疗达到预期的目标结果，并减少治疗结果的变异性。这有望成为医生的潜在有用工具。
