Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized, Double-blind, Parallel-group Study

Abstract

Purpose: The objective of this study was to assess pharmacokinetic (PK) and safety profiles of 2 fixed-dose combinations in development for the treatment of chronic obstructive pulmonary disease (COPD): budesonide/glycopyrronium/formoterol fumarate dihydrate metered-dose inhaler (BGF MDI; triple combination) and glycopyrronium/formoterol fumarate dihydrate (GFF MDI; dual combination). The PK and safety profiles of BGF MDI and GFF MDI were assessed for the first time in healthy Chinese adults after single and repeated (7-day) dosing.

Methods: This Phase I, randomized, double-blind, parallel-group study was conducted at a single site in Shanghai, China. Male or female Chinese subjects, 18-45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 μg, BGF MDI 160/14.4/10 μg, or GFF MDI 14.4/10 μg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC_0-12, C_max, and T_max. Tolerability was assessed using physical examination findings, adverse events reporting, 12-lead ECG, vital signs, and clinical laboratory values.

Findings: Ninety-six subjects (mean age, 25.6 years; 83.3% male) were randomized and received treatment. All randomized subjects were included in the safety and PK populations. After single and repeated dosing, budesonide AUC_0-12 and C_max were increased dose proportionally from BGF MDI 160/14.4/10 μg to BGF MDI 320/14.4/10 μg, respectively (single dose: AUC_0-12, 811.8 vs 1748 h · pg/mL; C_max, 224.3 vs 459.3 pg/mL; repeated dosing: AUC_0-12, 1250 vs 2510 h · pg/mL; C_max, 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC_0-12 and C_max were similar across all treatments (single dose: AUC_0-12, 27.20-29.40 h · pg/mL; C_max, 4.884-5.674 pg/mL; repeated dosing: AUC_0-12, 69.49-77.08 h · pg/mL; C_max, 11.30-13.12 pg/mL) and formoterol (single dose: AUC_0-12, 46.49-53.58 h · pg/mL; C_max 9.651-10.62 pg/mL; repeated dosing: AUC_0-12, 81.94-85.32 h · pg/mL; C_max, 16.13-17.71 pg/mL), suggesting that the addition of budesonide did not appreciably alter the PK properties of GFF MDI. All treatment-emergent adverse events were mild in severity and rates were similar across groups (range, 50.0%-56.3%). There were no new or unexpected findings on tolerability.

Implications: Overall, all treatments were well tolerated and PK parameters were generally comparable to those previously reported in Western and Japanese healthy subjects, suggesting that the doses of BGF MDI and GFF MDI in development globally for COPD are also appropriate for Chinese patients with COPD. ClinicalTrials.gov identifier: NCT03075267.

Keywords: budesonide; chronic obstructive pulmonary disease; co-suspension delivery technology; formoterol fumarate; glycopyrrolate; pharmacokinetics.