Center of Clinical Pharmacology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Department of Pharmacy, the Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
Pulm Pharmacol Ther. 2020 Apr;61:101902. doi: 10.1016/j.pupt.2020.101902. Epub 2020 Feb 8.
Indacaterol is one of the long-acting beta-adrenergic agonists, referred as first-line monotherapy for Chronic obstructive pulmonary disease since 2011. Generic products are encouraged to benefit the large COPD patients in China, in which can provide more choices association with reduced cost and improve the quality of patient life.
The three-part study consists of two independent cohorts of thirty-six subjects, aimed to evaluate the bioequivalence (BE) of two indacaterol formulations in gastrointestinal (GI) absorption charcoal-block or non-block conditions. One pilot study performed in six healthy subjects to determine the blocking effect of a new charcoal-based regimen on GI absorption after orally inhalation of indacaterol.
Two BE studies were conducted with a randomized, open-label, 2-period crossover design in two independent 36-healthy-subject cohorts, equivalence in systemic and lung deposition was assessed after inhalation of a single dose of 150 μg indacaterol (test or reference formulation) alone or concomitant administration of charcoal. The charcoal-based regimen was improved by optimizing the dose and number of doses, and its blocking efficacy against GI absorption was assessed in a pilot study. Six healthy subjects received 9 g charcoal 10 min before, immediately after and 2 h after indacaterol (3 g/100 ml water × 3 times). Blood collected at predetermined time points up to 72 h. Plasma indacaterol concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Equivalences were concluded if the 90% confidence interval (CI) for test: reference of C and AUC fell within the limits of 0.8-1.25.
Indacaterol was undetectable in plasma samples in pilot study. The T/R ratio of the geometric mean C and AUC was 109.9% (90% CI, 106.1-113.8%) and 104.8% (90% CI, 101.5-108.1%) for charcoal-block subjects and 105.4% (90% CI, 99.8% ~ 111.3%), and 101.0% (90% CI, 97.7%-104.4%) for non-block subjects. No serious adverse events were reported.
The results showed that 150 μg indacaterol (+/- 9 g charcoal) was well tolerated in all subjects. The two formulations are bioequivalent in terms of the rate and absorption both in charcoal-block and non-block conditions. The improved charcoal-based regimen demonstrated to be effective and fully blockade of GI absorption of indacaterol.
自 2011 年以来，茚达特罗作为长效β-肾上腺素能激动剂之一，被推荐为慢性阻塞性肺疾病的一线单药治疗药物。仿制药的鼓励使用将使中国大量 COPD 患者受益，从而提供更多的选择，降低成本，提高患者的生活质量。
本研究由两部分组成，共有 36 名受试者，旨在评估两种茚达特罗制剂在胃肠道（GI）吸收炭阻断或非阻断条件下的生物等效性（BE）。一项初步研究在 6 名健康受试者中进行，以确定新的基于炭的方案在口服吸入茚达特罗后对 GI 吸收的阻断作用。
在两个独立的 36 名健康受试者队列中，进行了两项 BE 研究，采用随机、开放标签、2 期交叉设计，评估单次吸入 150μg 茚达特罗（试验或参比制剂）或同时给予炭后的全身和肺部沉积的等效性。通过优化剂量和剂量次数，对基于炭的方案进行了改进，并在初步研究中评估了其对 GI 吸收的阻断作用。6 名健康受试者在吸入茚达特罗前 10 分钟、吸入后立即和 2 小时给予 9g 炭（100ml 水×3 次/3g）。在 72 小时内的预定时间点采集血样。使用 HPLC-MS/MS 测定血浆茚达特罗浓度。采用非房室分析计算药代动力学参数。如果试验：参考 C 和 AUC 的 90%置信区间（CI）落在 0.8-1.25 范围内，则得出等效结论。
初步研究中，血浆样本中未检测到茚达特罗。炭阻断组和非阻断组的 C 和 AUC 的几何均数 T/R 比值分别为 109.9%（90%CI，106.1-113.8%）和 104.8%（90%CI，101.5-108.1%），105.4%（90%CI，99.8%-111.3%）和 101.0%（90%CI，97.7%-104.4%）。未报告严重不良事件。
结果表明，所有受试者均耐受 150μg 茚达特罗（±9g 炭）。两种制剂在炭阻断和非阻断条件下的吸收速率和吸收均具有生物等效性。改进的基于炭的方案显示出有效性，并能完全阻断茚达特罗的 GI 吸收。
