Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.
Richmond Pharmacology, London, United Kingdom; St. George's University, London, United Kingdom.
Clin Ther. 2021 Nov;43(11):1934-1947.e4. doi: 10.1016/j.clinthera.2021.09.001. Epub 2021 Sep 29.
A number of single-inhaler, fixed-dose, triple combinations are available for the management of chronic obstructive pulmonary disease and/or asthma. One of these is the extrafine formulation beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide (BDP/FF/GB). Given that differences in ethnicity can result in differences in systemic exposure, we evaluated the relative pharmacokinetic (PK) profiles of BDP/FF/GB in Japanese vs Caucasian healthy volunteers to assess the need for dose adjustment.
This randomized, double-blind, single-dose, 4-way crossover study recruited healthy men and women 20 to 55 years of age; for each Japanese person a Caucasian was enrolled who matched in terms of sex, age, and weight. Study treatments included BDP/FF/GB 200/12/25 and 400/12/25 μg (therapeutic), 800/48/100 μg (supratherapeutic), and placebo. PK blood samples were taken up to 24 hours for evaluation of BDP, beclomethasone 17-monopropionate (B17MP, an active metabolite of BDP), and formoterol and up to 48 h for GB. The primary objective was to characterize the PK profiles of BDP, FF, and GB after administration of a single dose of BDP/FF/GB in Caucasian and Japanese healthy volunteers in terms of the AUC and C of B17MP, formoterol, and GB.
Of the 32 recruited participants (16 Japanese and 16 Caucasian ), 30 completed the study. A clear plasma exposure dose-response relationship was found for all 4 molecules. B17MP C geometric mean ratios for Japanese vs Caucasian participants for the 3 study treatments ranged from 1.17 to 1.26, and AUC ratios ranged from 1.16 to 1.22; thus, the findings were comparable between the ethnicities. Formoterol exposure was higher in Japanese than Caucasian participants (C, 1.22-1.53; AUC, 1.23-1.40). The GB C with BDP/FF/GB 400/12/25 μg (1.09) and AUC values for all three doses (0.98-1.17) were comparable in the 2 populations, but C with 200/12/25 and 800/48/100 μg were higher in Japanese participants (1.32 and 1.42, respectively). Pharmacodynamic (cortisol, potassium, glucose, blood pressure, heart rate, and QT interval with the Fridericia correction) and safety profile results were similar in the 2 ethnicities, with most patients not experiencing any adverse events.
Exposure to BDP/FF/GB pressurized metered dose inhaler at therapeutic and supratherapeutic doses was associated with higher plasma levels in Japanese versus Caucasian healthy volunteers. These PK differences did not translate into meaningful differences in the safety or pharmacodynamic parameters assessed in this study and were consistent with the results of other long-term (52-week) published studies. Dose adjustments in Japanese people are not deemed necessary. CLINICALTRIALS.
NCT03859414.
有许多单吸入器、固定剂量、三联组合可用于治疗慢性阻塞性肺疾病和/或哮喘。其中之一是倍氯米松二丙酸酯、富马酸福莫特罗、格隆溴铵的超细制剂（BDP/FF/GB）。由于种族差异可能导致全身暴露的差异，我们评估了 BDP/FF/GB 在日本和白种人健康志愿者中的相对药代动力学（PK）特征，以评估是否需要调整剂量。
这是一项随机、双盲、单剂量、4 向交叉研究，招募了 20 至 55 岁的健康男性和女性；为每个日本人招募了一名在性别、年龄和体重方面与之匹配的白种人。研究治疗包括 BDP/FF/GB 200/12/25 和 400/12/25μg（治疗）、800/48/100μg（超治疗）和安慰剂。在 24 小时内采集 PK 血样，以评估 BDP、倍氯米松 17-单丙酸酯（B17MP，BDP 的活性代谢物）和福莫特罗的 PK，并在 48 小时内采集 GB 的 PK。主要目的是描述 BDP/FF/GB 在白种人和日本健康志愿者中的单次剂量给药后的 PK 特征，包括 B17MP、福莫特罗和 GB 的 AUC 和 C。
在 32 名入组的参与者（16 名日本人，16 名白种人）中，有 30 名完成了研究。发现所有 4 种分子都存在明显的血浆暴露剂量反应关系。日本参与者与白种人参与者的 B17MP 几何均数比值范围为 1.17 至 1.26，AUC 比值范围为 1.16 至 1.22；因此，两种族之间的结果相当。与白种人参与者相比，福莫特罗在日本人中的暴露量更高（C，1.22-1.53；AUC，1.23-1.40）。BDP/FF/GB 400/12/25μg（1.09）和所有三种剂量的 AUC 值（0.98-1.17）的 GB C 在两个人群中相似，但 200/12/25 和 800/48/100μg 的 C 值在日本人中更高（分别为 1.32 和 1.42）。在两种族中，药效学（皮质醇、钾、葡萄糖、血压、心率和 Fridericia 校正后的 QT 间期）和安全性概况结果相似，大多数患者没有出现任何不良事件。
在接受治疗和超治疗剂量的 BDP/FF/GB 压力计量吸入器治疗时，日本人的 BDP/FF/GB 血浆水平高于白种人健康志愿者。这些 PK 差异并未转化为评估的安全性或药效学参数的有意义差异，与其他长期（52 周）已发表研究的结果一致。日本人不需要调整剂量。临床试验。
NCT03859414。
