Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetics/Pharmacodynamics, Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
Translational Medicine, Novartis Institutes for BioMedical Research, Horsham, West Sussex, UK.
Clin Pharmacol Drug Dev. 2016 Jul;5(4):285-95. doi: 10.1002/cpdd.245. Epub 2016 Jan 22.
This single-dose, 4-period crossover study evaluated the pharmacokinetics (PK) of the β2 -agonist indacaterol maleate and the corticosteroid mometasone furoate (MF) after inhalation of a fixed-dose combination (QMF149, indacaterol maleate/MF, 500/400 μg) via the Twisthaler (TH) device with and without activated charcoal and postdose mouth rinsing in healthy volunteers. The PK of indacaterol maleate 300 μg inhaled via the Breezhaler (BRZ) device was also characterized. Relative bioavailability of indacaterol and MF for inhalation with versus without charcoal, based on AUClast, was 0.25 (90% confidence interval [CI], 0.18-0.35) and 0.70 (90%CI, 0.52-0.93), respectively. Thus, 25% and 70% of systemic exposure of indacaterol and MF, respectively was due to pulmonary absorption and 75% and 30%, respectively, was due to gastrointestinal absorption. Mouth rinsing reduced the systemic exposure of indacaterol by approximately 35% but had no relevant effect on the exposure of MF. Dose-normalized AUClast for indacaterol inhaled via the BRZ device was 2.3-fold higher than QMF149 via the TH device. All treatments had a good safety profile and were well tolerated. Data from this study and comparison with inhalation of indacaterol via the BRZ device suggest that the latter was more efficient than the TH device regarding lung delivery of indacaterol.
这项单次、4 期交叉研究评估了固定剂量组合（QMF149，马来酸茚达特罗/糠酸莫米松，500/400μg）经 Twisthaler（TH）装置吸入并联合或不联合活性炭以及用药后漱口时，马来酸茚达特罗（β2-激动剂）和糠酸莫米松（皮质类固醇）的药代动力学（PK）在健康志愿者中的变化。还对 Breezhaler（BRZ）装置吸入 300μg 马来酸茚达特罗的 PK 特征进行了描述。基于 AUClast，与不联合活性炭相比，TH 装置吸入时，马来酸茚达特罗和糠酸莫米松的相对生物利用度分别为 0.25（90%置信区间[CI]，0.18-0.35）和 0.70（90%CI，0.52-0.93）。因此，马来酸茚达特罗和糠酸莫米松的系统暴露量分别有 25%和 70%来自肺部吸收，分别有 75%和 30%来自胃肠道吸收。漱口使马来酸茚达特罗的系统暴露量减少了约 35%，但对糠酸莫米松的暴露量没有相关影响。经 BRZ 装置吸入时，马来酸茚达特罗的剂量标准化 AUClast 是经 TH 装置时 QMF149 的 2.3 倍。所有治疗方案均具有良好的安全性和耐受性。该研究数据与经 BRZ 装置吸入茚达特罗的研究结果进行比较，表明后者在肺部输送马来酸茚达特罗方面比 TH 装置更有效。
