School of Chemical Engineering, Oklahoma State University, USA; Office of Pharmaceutical Quality, Center for Drug Evaluation Research, US Food and Drug Administration, USA.
School of Chemical Engineering, Oklahoma State University, USA.
Comput Biol Med. 2021 May;132:104333. doi: 10.1016/j.compbiomed.2021.104333. Epub 2021 Mar 13.
Predicting the optimal administration doses of the inhaled Δ9-tetrahydrocannabinol (THC), i.e., one of the major natural compounds in cannabis, is critical for maximizing the therapeutic outcomes and minimizing the toxic side effects. Thus, it is essential to developing an aerosol dosimetry model to simulate the transport, deposition, and translocation of inhaled THC aerosols from the human respiratory system to the systemic region. In this study, a computational fluid-particle dynamics (CFPD) plus pharmacokinetics (PK) model was developed and validated to quantify the localized vapor and particle uptake rates of THC and the resultant THC-plasma concentrations using two human upper airway geometries. In addition, two different puff protocols (4.0/10.0 s and 1.6/11.4 s as the inhalation/holding time ratios) were employed, associated with two different inhaled THC doses (2.0 mg and 8.82 mg, respectively). The computational results demonstrated that multiple parameters had noticeable influences on THC particle deposition and vapor absorption in the upper airways, as well as the resultant pharmacokinetic behaviors. These factors include anatomical features of the upper airway, puff flow rate, duration, and holding time. The results indicated that puff protocol with 4.0/10.0 s inhalation/holding time ratio would be recommended if the treatment needs THC delivery to the deeper lung. Furthermore, the inhaled THC dose had a dominant effect on the THC-plasma PK profiles, which could override the influences of anatomical variability and puff protocols. The developed CFPD-PK modeling framework has the potential to provide localized lung absorption data and PK profiles for in vitro-in vivo correlation, as well as supporting the development and assessment of drug products containing cannabis or cannabis-derived compounds.
预测吸入大麻中主要天然化合物之一 Δ9-四氢大麻酚（THC）的最佳给药剂量对于最大限度地提高治疗效果和最小化毒性副作用至关重要。因此，开发一种气溶胶药物计量学模型来模拟从人体呼吸系统到全身区域的吸入 THC 气溶胶的传输、沉积和转运至关重要。在这项研究中，开发并验证了一个计算流体-颗粒动力学（CFPD）加药代动力学（PK）模型，以量化 THC 的局部蒸汽和颗粒摄取率以及由此产生的 THC-血浆浓度，使用两种人体上呼吸道几何形状。此外，采用了两种不同的抽吸方案（4.0/10.0 s 和 1.6/11.4 s 作为吸入/保持时间比），分别与两种不同的吸入 THC 剂量（2.0 mg 和 8.82 mg）相关联。计算结果表明，多个参数对上呼吸道中 THC 颗粒沉积和蒸汽吸收以及由此产生的药代动力学行为有明显影响。这些因素包括上呼吸道的解剖特征、抽吸流速、持续时间和保持时间。结果表明，如果治疗需要将 THC 输送到更深的肺部，则推荐使用 4.0/10.0 s 吸入/保持时间比的抽吸方案。此外，吸入 THC 剂量对 THC-血浆 PK 曲线有主导作用，可以覆盖解剖变异性和抽吸方案的影响。所开发的 CFPD-PK 建模框架有可能提供局部肺吸收数据和 PK 曲线，以进行体外-体内相关性，以及支持含有大麻或大麻衍生化合物的药物产品的开发和评估。
