GlaxoSmithKline, Collegeville, Pennsylvania, USA.
GlaxoSmithKline, Middlesex, United Kingdom.
Antimicrob Agents Chemother. 2020 Apr 21;64(5). doi: 10.1128/AAC.02267-19.
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition, causing progressive decline in lung function leading to premature death. Acute exacerbations in COPD patients are predominantly associated with respiratory viruses. Ribavirin is a generic broad-spectrum antiviral agent that could be used for treatment of viral respiratory infections in COPD. Using the Particle Replication In Nonwetting Templates (PRINT) technology, which produces dry-powder particles of uniform shape and size, two new inhaled formulations of ribavirin (ribavirin-PRINT-CFI and ribavirin-PRINT-IP) were developed for efficient delivery to the lung and to minimize bystander exposure. Ribavirin-PRINT-CFI was well tolerated in healthy participants after single dosing and ribavirin-PRINT-IP was well tolerated in healthy and COPD participants after single and repeat dosing. Ribavirin-PRINT-CFI was replaced with ribavirin-PRINT-IP since the latter formulation was found to have improved physicochemical properties and it had a higher ratio of active drug to excipient per unit dose. Ribavirin concentrations were measured in lung epithelial lining fluid in both healthy and COPD participants and achieved target concentrations. Both formulations were rapidly absorbed with approximately dose proportional pharmacokinetics in plasma. Exposure to bystanders was negligible based on both the plasma and airborne ribavirin concentrations with the ribavirin-PRINT-IP formulation. Thus, ribavirin-PRINT-IP allowed for an efficient and convenient delivery of ribavirin to the lungs while minimizing systemic exposure. Further clinical investigations would be required to demonstrate ribavirin-PRINT-IP antiviral characteristics and impact on COPD viral-induced exacerbations. (The clinical trials discussed in this study have been registered at ClinicalTrials.gov under identifiers NCT03243760 and NCT03235726.).
慢性阻塞性肺疾病（COPD）是一种肺部炎症性疾病，导致肺功能进行性下降，导致过早死亡。COPD 患者的急性加重主要与呼吸道病毒有关。利巴韦林是一种通用的广谱抗病毒药物，可用于治疗 COPD 中的病毒呼吸道感染。使用产生均匀形状和大小的干粉颗粒的粒子复制非润湿模板（PRINT）技术，开发了两种新的利巴韦林吸入制剂（利巴韦林-PRINT-CFI 和利巴韦林-PRINT-IP），用于有效递送至肺部，并尽量减少旁观者暴露。利巴韦林-PRINT-CFI 在单次给药后在健康参与者中具有良好的耐受性，利巴韦林-PRINT-IP 在健康和 COPD 参与者单次和重复给药后具有良好的耐受性。由于后一种制剂被发现具有改进的物理化学性质，并且其单位剂量的活性药物与赋形剂的比例更高，因此利巴韦林-PRINT-CFI 被利巴韦林-PRINT-IP 替代。在健康和 COPD 参与者的肺上皮衬里液中均测量了利巴韦林浓度，并达到了目标浓度。两种制剂在血浆中均具有快速吸收作用，接近剂量比例的药代动力学。基于利巴韦林-PRINT-IP 制剂的血浆和空气传播的利巴韦林浓度，旁观者的暴露可以忽略不计。因此，利巴韦林-PRINT-IP 允许利巴韦林高效且方便地递送至肺部，同时最大限度地减少全身暴露。需要进一步的临床研究来证明利巴韦林-PRINT-IP 的抗病毒特征及其对 COPD 病毒诱导的加重的影响。（本研究中讨论的临床试验已在 ClinicalTrials.gov 上注册，标识符为 NCT03243760 和 NCT03235726。）
