Novel tobramycin inhalation powder in cystic fibrosis subjects: Pharmacokinetics and safety
Novel tobramycin inhalation powder in cystic fibrosis subjects: Pharmacokinetics and safety
复制标题
DOI：
10.1002/ppul.20594
复制
发表时间：
2007-04-01
影响因子：
3.1
通讯作者：
Conrad, Carol
中科院分区：
文献类型：
--
作者：
Geller, David E.;Konstan, Michael W.;Conrad, Carol
雾化抗生素与高治疗负担相关，可能导致不坚持长期治疗。我们评估了妥布霉素吸入粉剂 (TIP) 的药代动力学 (PK) 和安全性，这是一种新型干粉制剂，旨在将高有效负载的妥布霉素局部输送到肺部，用于治疗慢性铜绿假单胞菌感染。这是一项多中心、开放标签、序贯队列、单剂量、剂量递增研究，使用标准 300 mg 剂量的妥布霉素吸入溶液 (TSI) 作为活性对照。受试者在 5 个队列中以 3:1 的比例随机分配至 TIP 或 TSI。测量包括血清和痰液妥布霉素浓度、给药时间、血清化学成分、肺功能的急性变化和不良事件 (AE)。在 90 名随机受试者中，86 名有安全性分析数据； 84 人有 PK 分析数据。 TIP 和 TSI 的血清妥布霉素 PK 曲线相似。四粒 28 mg TIP 胶囊（妥布霉素总剂量 112 mg）在不到三分之一的给药时间内产生与 300 mg TSI 相当的全身暴露。与 TIP 相关的最常见 AE 是咳嗽 (20%) 和味觉障碍 (17%)。与 TSI 相比，TIP 可以更快、更有效地肺部输送妥布霉素，并且其安全性支持持续的临床研究。对于高有效负载粉末配方来说，TIP 引起的局部呼吸道刺激率增加并不令人意外。干粉吸入抗生素的开发可能代表了治疗慢性肺部感染的重要进展。
Aerosolized antibiotics are associated with a high treatment burden that can result in non-adherence to chronic therapy We evaluated the pharmacokinetics (PK) and safety of tobramycin inhalation powder (TIP), a novel dry-powder formulation designed to deliver a high payload of tobramycin topically to the lungs for management of chronic Pseudomonas aeruginosa infections. This was a multi-center, open-label, sequential-cohort, single-dose, dose-escalation study using the standard 300 mg dose of tobramycin solution for inhalation (TSI) as an active control. Subjects were randomized to TIP or TSI in a 3:1 ratio in each of five cohorts. Measurements included serum and sputum tobramycin concentrations, administration time, serum chemistries, acute change in lung function, and adverse events (AEs). Out of 90 randomized subjects, 86 had data for safety analysis; and 84 had data for PK analysis. Serum tobramycin PK profiles were similar for TIP and TSI. Four capsules of 28 mg TIP (total tobramycin dose 112 mg) produced comparable systemic exposure to 300 mg TSI, in less than one-third the administration time. The most common AEs associated with TIP were cough (20%) and dysgeusia (17%). TIP allows for faster and more efficient pulmonary delivery of tobramycin than TSI and has a safety profile that supports continued clinical investigation. The increased rate of local respiratory tract irritation noted with TIP is not unexpected with a high-payload powder formulation. The development of dry powder inhaled antibiotics may represent an important advance in the treatment of chronic lung infections.