Ethnic pharmacokinetic comparison of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) between Asian and Western healthy subjects

Pulm Pharmacol Ther. 2020 Oct;64:101976. doi: 10.1016/j.pupt.2020.101976. Epub 2020 Nov 2.

Abstract

Background: 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.

Methods: 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 [AUC0-12] and maximum plasma concentration, [Cmax]) 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.

Results: 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, AUC0-12 and Cmax 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 Cmax 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.

Conclusions: Overall, these analyses suggest no appreciable ethnic differences in the PK of BGF MDI across Chinese, Japanese and Western healthy subjects.

Keywords: Budesonide/glycopyrrolate/formoterol; COPD; Co-suspension delivery technology; Ethnic insensitivity study; Fixed-dose combination; Pharmacokinetics.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Bronchodilator Agents / therapeutic use
  • Budesonide / therapeutic use
  • Double-Blind Method
  • Drug Combinations
  • Formoterol Fumarate / therapeutic use
  • Fumarates / therapeutic use
  • Glycopyrrolate* / therapeutic use
  • Healthy Volunteers
  • Humans
  • Metered Dose Inhalers
  • Pulmonary Disease, Chronic Obstructive* / drug therapy

Substances

  • Bronchodilator Agents
  • Drug Combinations
  • Fumarates
  • Budesonide
  • Glycopyrrolate
  • Formoterol Fumarate

Associated data

  • ClinicalTrials.gov/NCT02497001
  • ClinicalTrials.gov/NCT03075267
  • ClinicalTrials.gov/NCT02197975
  • ClinicalTrials.gov/NCT01980615
  • ClinicalTrials.gov/NCT02189304