Hasan M A, Lange C F
Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta, Canada.
J Aerosol Med. 2007 Fall;20(3):282-93. doi: 10.1089/jam.2007.0603.
Antibiotic drugs exhibit concentration dependence in their efficacy. Therefore, ensuring appropriate concentration of these drugs in the relevant body fluid is important for obtaining the desired therapeutic and physiological action. Until recently there had been no suitable method available to measure or estimate concentration of drugs in the human airways resulting from inhaled aerosols or to determine the amount of inhaled antibiotics required to ensure minimum inhibitory concentration of a drug in the airway surface liquid (ASL). In this paper a numerical method is used for estimating local concentration of inhaled pharmaceutical aerosols in different generations of the human tracheobronchial airways. The method utilizes a mathematical lung deposition model to estimate amounts of aerosols depositing in different lung generations, and a recent ASL model along with deposition results to assess the concentration of deposited drugs immediately following inhalation. Examples of concentration estimates for two case studies: one for the antibiotic tobramycin against Pseudomonas aeruginosa, and another for taurolidine against Burkholderia cepacia are presented. The aerosol characteristics, breathing pattern and properties of nebulized solutions were adopted from two recent clinical studies on efficacy of these drugs in cystic fibrosis (CF) patients and from other sources in the literature. While the clinically effective tobramycin showed a concentration higher than the required in vivo concentration, that for the ineffective taurolidine was found to be below the speculated required in vivo concentration. Results of this study thus show that the mathematical ASL model combined with the lung deposition model can be an effective tool for helping decide the optimum dosage of inhaled antibiotic drugs delivered during human clinical trials.
抗生素药物的疗效呈现浓度依赖性。因此，确保这些药物在相关体液中达到适当浓度对于获得理想的治疗和生理作用至关重要。直到最近，还没有合适的方法来测量或估计吸入气雾剂在人体气道中产生的药物浓度，也无法确定为确保气道表面液体（ASL）中药物的最低抑菌浓度所需的吸入抗生素剂量。本文采用一种数值方法来估计人类气管支气管气道不同代中吸入药物气雾剂的局部浓度。该方法利用数学肺沉积模型来估计沉积在不同肺代中的气雾剂数量，并结合最近的ASL模型和沉积结果结果来评估吸入后立即沉积的药物浓度。给出了两个案例研究的浓度估计示例：一个是针对抗铜绿假单胞菌的抗生素妥布霉素，另一个是针对洋葱伯克霍尔德菌的牛磺罗定。气雾剂特性、呼吸模式和雾化溶液的性质取自最近两项关于这些药物在囊性纤维化（CF）患者中疗效的临床研究以及文献中的其他来源。虽然临床上有效的妥布霉素显示的浓度高于体内所需浓度，但无效的牛磺罗定的浓度低于推测的体内所需浓度。因此，本研究结果表明，数学ASL模型与肺沉积模型相结合可以成为帮助确定人类临床试验期间吸入抗生素药物最佳剂量的有效工具。
