AstraZeneca, Liangjing Rd, Pudong Xinqu, Shanghai Shi, China.
AstraZeneca, 4222 Emperor Blvd, Suite 560, Durham, NC, 27703, USA.
Pulm Pharmacol Ther. 2020 Oct;64:101976. doi: 10.1016/j.pupt.2020.101976. Epub 2020 Nov 2.
The Phase III KRONOS study (NCT02497001) found the fixed-dose combination triple therapy budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) to be efficacious and well tolerated versus corresponding dual therapies in patients with moderate-to-very severe COPD from North America, China and Japan. However, pharmacokinetic (PK) studies of other drugs have shown that ethnic factors (e.g. genetic factors affecting drug metabolism) can affect the bioavailability of drugs which may impact upon efficacy and safety outcomes.
This was a post-hoc analysis of data from four randomised, double-blind Phase I studies of BGF MDI 320/18/9.6 μg and 160/18/9.6 μg in Chinese (NCT03075267), Japanese (NCT02197975) and Western (NCT01980615, NCT02189304) healthy subjects. PK properties (area under the plasma concentration-time curve 0-12 h post-dose [AUC] and maximum plasma concentration, [C]) were recorded following single and repeated dosing of BGF MDI 320/18/9.6 μg or 160/18/9.6 μg. Potential ethnic differences in the PK properties of budesonide, glycopyrrolate and formoterol in Chinese, Japanese and Western healthy subjects were derived by non-compartmental analysis, and ethnic insensitivity factors evaluated based on criteria from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline E5 Ethnic Factors in the Acceptability of Foreign Clinical Data.
The analyses included data from 64 Chinese, 31 Japanese and 169 Western subjects. Overall, PK properties following single or repeated dosing of BGF MDI were similar across Chinese, Japanese and Western subjects. After single dosing at either dose level, AUC and C for budesonide, glycopyrrolate and formoterol appeared generally similar for Asian (Chinese and Japanese) versus Western subjects, with most geometric least squares mean ratios within the range of 0.92-1.22. The exception was that C for glycopyrrolate was slightly lower in Asian versus Western subjects (0.6-0.7). Of the 10 ethnic insensitivity factors evaluated, six were met for budesonide, nine for glycopyrrolate and nine for formoterol, suggesting that BGF MDI can be classified as an ethnically insensitive drug.
Overall, these analyses suggest no appreciable ethnic differences in the PK of BGF MDI across Chinese, Japanese and Western healthy subjects.
III 期 KRONOS 研究（NCT02497001）发现，布地奈德/格隆溴铵/富马酸福莫特罗定量吸入粉雾剂（BGF MDI）固定剂量复方三联疗法在来自北美、中国和日本的中重度 COPD 患者中与相应的双联疗法相比具有疗效且耐受性良好。然而，其他药物的药代动力学（PK）研究表明，种族因素（例如影响药物代谢的遗传因素）可能会影响药物的生物利用度，从而影响疗效和安全性结局。
这是 BGF MDI 320/18/9.6μg 和 160/18/9.6μg 在中国（NCT03075267）、日本（NCT02197975）和西方（NCT01980615、NCT02189304）健康受试者的四项随机、双盲 I 期研究数据的事后分析。单次和重复使用 BGF MDI 320/18/9.6μg 或 160/18/9.6μg 后，记录布地奈德、格隆溴铵和福莫特罗的 PK 特性（给药后 0-12 小时的血浆浓度-时间曲线下面积[AUC]和最大血浆浓度 [C]）。通过非房室分析得出了布地奈德、格隆溴铵和福莫特罗在中国、日本和西方健康受试者中的 PK 特性的潜在种族差异，并根据人用药物技术要求国际协调理事会、E5 指导原则的标准评估了种族不敏感因素。在可接受性外国临床数据。
该分析包括 64 名中国、31 名日本和 169 名西方受试者的数据。总体而言，BGF MDI 单次或重复给药后的 PK 特性在中、日、西受试者之间相似。在两种剂量水平下单次给药后，布地奈德、格隆溴铵和福莫特罗的 AUC 和 C 在中国（中国和日本）和西方受试者之间基本相似，大多数几何均数比值在 0.92-1.22 范围内。例外是格隆溴铵的 C 在亚洲受试者中略低于西方受试者（0.6-0.7）。在评估的 10 个种族不敏感因素中，有 6 个符合布地奈德，9 个符合格隆溴铵，9 个符合福莫特罗，这表明 BGF MDI 可被归类为种族不敏感药物。
总体而言，这些分析表明，布地奈德/格隆溴铵/福莫特罗富马酸定量吸入粉雾剂在中、日、西健康受试者中的 PK 无明显种族差异。
