Ethnic Sensitivity Study of the Extrafine, Single-Inhaler, Triple Therapy Beclomethasone Dipropionate, Formoterol Fumarate, and Glycopyrronium Bromide Pressurized Metered Dose Inhaler in Japanese and Caucasian Healthy Individuals: A Randomized, Double-Blind, Single-Dose Crossover Study

Abstract

Purpose: 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.Methods: This randomized, double-blind, singledose, 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 0-t and C max of B17MP, formoterol, and GB.Findings: 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 max geometric mean ratios for Japanese vs Caucasian participants for the 3 study treatments ranged from 1.17 to 1.26, and AUC 0-t 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 max , 1.22-1.53; AUC 0-t , 1.23-1.40). The GB C max with BDP/FF/GB 400/12/25 μg (1.09) and AUC 0-t values for all three doses (0.98-1.17) were comparable in the 2 populations, but C max 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.Implications: 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 dif-

Asia‐Inclusive Global Development of Enpatoran: Results of an Ethno‐Bridging Study, Intrinsic/Extrinsic Factor Assessments and Disease Trajectory Modeling to Inform Design of a Phase II Multiregional Clinical Trial

“…The observed PK and IL‐6 response data from the ethno‐bridging study were generally consistent with predictions using the models developed from FIH data (White). The design of this ethno‐bridging study to examine the potential ethnic sensitivity in the PKs, PDs, and safety of enpatoran is consistent with others previously published, both in terms of sample size, 39,40 matching by age, sex, and weight, 39,40 and the use of healthy Japanese subjects to support inclusion of the wider Asian population into larger MRCTs 39–41 …”

“…7,8 The observed PK and IL-6 response data from the ethno-bridging study were generally consistent with predictions using the models developed from FIH data (White). The design of this ethno-bridging study to examine the potential ethnic sensitivity in the PKs, PDs, and safety of enpatoran is consistent with others previously published, both in terms of sample size, 39,40 matching by age, sex, and weight, 39,40 and the use of healthy Japanese subjects to support inclusion of the wider Asian population into larger MRCTs. [39][40][41] To enable Asia-inclusive drug development, it has been generally accepted by regulators, investigators, and drug developers, as a pragmatic approach, to use data from one East Asian population (e.g., Japanese) as initial evaluation of ethnic sensitivity, without generating data from multiple Asian populations upfront.…”

“…The design of this ethno-bridging study to examine the potential ethnic sensitivity in the PKs, PDs, and safety of enpatoran is consistent with others previously published, both in terms of sample size, 39,40 matching by age, sex, and weight, 39,40 and the use of healthy Japanese subjects to support inclusion of the wider Asian population into larger MRCTs. [39][40][41] To enable Asia-inclusive drug development, it has been generally accepted by regulators, investigators, and drug developers, as a pragmatic approach, to use data from one East Asian population (e.g., Japanese) as initial evaluation of ethnic sensitivity, without generating data from multiple Asian populations upfront. A recent analysis of 18 approved products revealed generally consistent PKs and dose recommendations across East Asian countries supporting the mutual use of clinical data among East Asian countries (specifically, the Chinese, Japanese, and Korean subpopulations).…”

Pharmacokinetics of extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide in adolescent and adult patients with asthma

“… 2 In addition, the pharmacokinetic (PK) profile of BDP/FF/GB has previously been investigated in adult healthy volunteers, with the dose‐adjusted PK profile similar for therapeutic and supra‐therapeutic doses, and no evidence of any impact of ethnicity on PK or safety parameters. 3 , 4 …”

“…In two 52‐week randomized clinical trials in adults with asthma that was uncontrolled by medium‐ or high‐dose ICS plus LABA, extrafine BDP/FF/GB improved lung function and reduced the rate of moderate‐and‐severe asthma exacerbations compared with extrafine BDP/FF 2 . In addition, the pharmacokinetic (PK) profile of BDP/FF/GB has previously been investigated in adult healthy volunteers, with the dose‐adjusted PK profile similar for therapeutic and supra‐therapeutic doses, and no evidence of any impact of ethnicity on PK or safety parameters 3,4 …”