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 fixeddose 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, 18e45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 mg, BGF MDI 160/14.4/10 mg, or GFF MDI 14.4/10 mg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC 0e12 , 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 0e12 and C max were increased dose proportionally from BGF MDI 160/14.4/10 mg to BGF MDI 320/14.4/10 mg, respectively (single dose: AUC 0e12 , 811.8 vs 1748 h $ pg/mL; C max , 224.3 vs 459.3 pg/mL; repeated dosing: AUC 0e12 , 1250 vs 2510 h $ pg/mL; C max , 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC 0e12 and C max were similar across all treatments (single dose: AUC 0e12 , 27.20e29.40 h $ pg/mL; C max , 4.884e5.674 pg/mL; repeated dosing: AUC 0e12 , 69.49e77.08 h $ pg/mL; C max , 11.30e13.12 pg/mL) and formoterol (single dose: AUC 0e12 , 46.49e53.58 h $ pg/mL; C max 9.651e10.62 pg/mL; repeated dosing: AUC 0e12 , 81.94e85.32 h $ pg/mL; C max, 16.13e17.71 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%e56.3%). 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. (Clin Ther. 2019;41:897e909)

Efficacy and Safety of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler in Chinese Patients with COPD: A Subgroup Analysis of KRONOS

“…Overall, treatments were well tolerated, with no new or unexpected safety findings, indicating that the safety profile of BGF MDI in Chinese patients was comparable to the wellestablished safety profiles of GFF MDI [21][22][23] and BUD/FORM DPI dual therapies [14][15][16]. The consistent safety profile between the Chinese and global KRONOS populations reflects the findings of a phase I pharmacokinetics study, which demonstrated that systemic exposures of budesonide, glycopyrronium, and formoterol in healthy Chinese adults were generally similar to those observed in Western subjects [24]. Similar to findings in the global population [9], the incidence of pneumonia was low overall and similar in the budesonide-containing treatment groups versus the GFF MDI group, suggesting that BGF MDI was not associated with an appreciably increased risk of pneumonia relative to dual LAMA/LABA therapy.…”

“…Changes from baseline in SGRQ total score occurred in all treatment groups (Table 3), with numerical improvements for BGF MDI versus GFF MDI and BFF MDI, and a nominally significant improvement versus BUD/FORM DPI (Table 3). TDI focal scores over weeks [12][13][14][15][16][17][18][19][20][21][22][23][24] showed improvements in all treatment groups (range 1.87-3.00); BGF MDI showed a small numerical improvement versus GFF MDI and a nominally significant improvement versus BUD/FORM DPI. BGF MDI demonstrated nominally significant improvement in change from baseline in average daily rescue medication use over 24 weeks versus BFF MDI and numerical improvements versus GFF MDI and BUD/FORM DPI (Table 3).…”

“…For the primary endpoint (change from baseline in morning pre-dose trough FEV 1 over weeks [12][13][14][15][16][17][18][19][20][21][22][23][24], BGF MDI demonstrated nominally significant improvements versus BFF MDI (least squares mean (LSM) treatment difference 68 mL; P = 0.0035) and BUD/FORM DPI (LSM difference 78 mL; P = 0.0010) but not GFF MDI (LSM difference -4 mL; P = 0.8316; Table 2, Fig. 1a).…”

“…Findings according to the pre-specified Japan/ China statistical analysis approach are reported. Most endpoints were assessed over weeks 12-24. The primary efficacy endpoint was change from baseline in morning pre-dose trough FEV 1 over weeks [12][13][14][15][16][17][18][19][20][21][22][23][24]. Secondary lung function endpoints included change from baseline in morning pre-dose trough FEV 1 over 24 weeks, FEV 1 area under the curve from 0 to 4 h (AUC 0-4 ) over weeks 12-24, peak change from baseline in FEV 1 within 4 h post-dose over weeks [12][13][14][15][16][17][18][19][20][21][22][23][24], and time to onset of action (the first time point at which the change from baseline in FEV 1 was greater than 100 mL) on day 1.…”

Exposure-Response and Clinical Outcome Modeling of Inhaled Budesonide/Formoterol Combination in Asthma Patients

“…There are previous studies about the population PK model or PK/PD model of each drug. But these studies did not have PD effect data [20,21] or a developed PK/PD model of corticosteroid or LABA separately, even though these drugs are used as a combination therapy [22,23]. And none of them have a clinical outcome data or model, which is the crucial point to determine drug exposure-response relationship with this chronic disease.In this study, a prospective clinical trial data from adult moderate asthma patients were utilized to establish a population PK/PD/CO model for quantifying the exposure-response and disease progression relationship after inhalation of budesonide (a corticosteroid) and formoterol (a LABA).…”