通过两种干粉吸入器给予糠酸莫米松的药代动力学。
Pharmacokinetics of mometasone furoate delivered via two dry powder inhalers.
机构信息
Novartis Institutes for BioMedical Research, Cambridge, MA, United States.
Novartis Pharma AG, Basel, Switzerland.
出版信息
Pulm Pharmacol Ther. 2021 Oct;70:102019. doi: 10.1016/j.pupt.2021.102019. Epub 2021 Mar 23.
BACKGROUND
QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler®, under development for once-daily treatment of asthma. MF delivered via Twisthaler® is approved as Asmanex® Twisthaler® for the treatment of asthma. Bridging of MF delivered via Twisthaler® to MF delivered via Breezhaler® was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients.
OBJECTIVES
The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler® (50-400 μg) and compared systemic exposure of MF following administration via Breezhaler® and Twisthaler® 400 μg (2 inhalations of 200 μg). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler® and Twisthaler® devices for 4 weeks.
METHODS
In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler® (400 μg, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler® (50, 100, 200, 400 μg). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 μg (low-dose ICS) or 320 μg (high-dose ICS) via Breezhaler®, or 200 μg (low-dose ICS) or 800 μg (2 inhalations of 400 μg; high-dose ICS) via Twisthaler® once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose.
RESULTS
In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUC of MF was 1.8-1.9-fold higher when delivered via Breezhaler® versus Twisthaler®. AUC and C of MF increased in a dose-proportional manner over the range of 50-400 μg via Breezhaler®. Results from this study guided dose selection of MF via Breezhaler® for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUC and C) for MF 80 and 320 μg via Breezhaler® was comparable with MF 200 and 800 μg via Twisthaler®, respectively, on Day 28.
CONCLUSION
PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 μg (low), 160 μg (medium), and 320 μg (high) delivered via Breezhaler® as MF doses comparable to the 200 μg, 400 μg and 800 μg doses delivered by Twisthaler®, respectively, as part of QMF149 formulation development.
背景
QMF149 是一种通过 Breezhaler® 吸入的固定剂量组合药物，包含乙酰半胱氨酸和糠酸莫米松（MF），用于治疗哮喘，每日一次给药。通过 Twisthaler® 吸入的 MF 已被批准为 Asmanex® Twisthaler®，用于治疗哮喘。在 QMF149 的开发过程中，开展了 MF 从 Twisthaler® 到 Breezhaler® 的桥接研究，以实现设备之间的剂量比较。MF 的药代动力学（PK）特征在两项研究中进行了描述；一项是在健康志愿者中的单次剂量 PK 研究，另一项是在哮喘患者中的 PK/药效学（PK/PD）研究。
目的
在健康志愿者中的 PK 研究评估了通过 Breezhaler®（50-400μg）给予单剂量 MF 的 PK，并比较了通过 Breezhaler®和 Twisthaler® 400μg（2 次吸入 200μg）给药后 MF 的全身暴露情况。在哮喘患者中的研究描述了通过 Breezhaler®和 Twisthaler®设备每日一次吸入 MF 4 周后的 MF PK 特征。
方法
在开放标签、单次剂量、交叉研究中，健康受试者依次接受了通过 Twisthaler®（400μg，中剂量吸入性皮质类固醇[ICS]）和递增剂量通过 Breezhaler®（50、100、200、400μg）给予的 MF。在给药后 72 小时内获得 PK 数据。在双盲、双模拟、平行组研究中，哮喘患者随机接受 MF 80μg（低剂量 ICS）或 320μg（高剂量 ICS）通过 Breezhaler®，或 200μg（低剂量 ICS）或 800μg（2 次吸入 400μg；高剂量 ICS）通过 Twisthaler®，每日一次，共 4 周。在第 1 天和第 28 天进行 PK 采样，在给药前和给药后 24 小时进行。
结果
在健康志愿者 PK 研究中，20 名健康受试者完成了所有治疗。与通过 Twisthaler®相比，通过 Breezhaler®给予的 MF 的 AUC 和 C 的剂量归一化比值为 1.8-1.9 倍。通过 Breezhaler®，MF 的 AUC 和 C 在 50-400μg 范围内呈剂量比例增加。该研究的结果指导了用于哮喘研究的 MF 通过 Breezhaler®的剂量选择。在哮喘研究中，在 96 名患者的亚组中，在第 28 天，通过 Breezhaler®给予的 MF 80 和 320μg 的系统暴露（AUC 和 C）与通过 Twisthaler®给予的 MF 200 和 800μg 相当。
结论
在健康志愿者 PK 研究中的 PK 特征描述以及随后在哮喘研究中的特征描述，使通过 Breezhaler®给予的 80μg（低）、160μg（中）和 320μg（高）剂量被选择为与通过 Twisthaler®给予的 200μg、400μg 和 800μg 剂量相当的剂量，分别作为 QMF149 制剂开发的一部分。
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