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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 AUC0-12, Cmax, and Tmax. 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 AUC0-12 and Cmax were increased dose proportionally from BGF MDI 160/14.4/10 μg to BGF MDI 320/14.4/10 μg, respectively (single dose: AUC0-12, 811.8 vs 1748 h · pg/mL; Cmax, 224.3 vs 459.3 pg/mL; repeated dosing: AUC0-12, 1250 vs 2510 h · pg/mL; Cmax, 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC0-12 and Cmax were similar across all treatments (single dose: AUC0-12, 27.20-29.40 h · pg/mL; Cmax, 4.884-5.674 pg/mL; repeated dosing: AUC0-12, 69.49-77.08 h · pg/mL; Cmax, 11.30-13.12 pg/mL) and formoterol (single dose: AUC0-12, 46.49-53.58 h · pg/mL; Cmax 9.651-10.62 pg/mL; repeated dosing: AUC0-12, 81.94-85.32 h · pg/mL; Cmax, 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.

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  • Authors+Show Affiliations

    ,

    Central Laboratory, Shanghai Xuhui District Central Hospital, Shanghai, China.

    ,

    Central Laboratory, Shanghai Xuhui District Central Hospital, Shanghai, China.

    ,

    AstraZeneca, Shanghai, China.

    ,

    AstraZeneca, Shanghai, China.

    ,

    AstraZeneca, Shanghai, China.

    ,

    AstraZeneca, Gaithersburg, MD, USA.

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    Central Laboratory, Shanghai Xuhui District Central Hospital, Shanghai, China.

    AstraZeneca, Durham, NC, USA. Electronic address: paul.dorinsky1@astrazeneca.com.

    Source

    Clinical therapeutics 41:5 2019 May pg 897-909.e1

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    30982547

    Citation

    Chen, Qian, et al. "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." Clinical Therapeutics, vol. 41, no. 5, 2019, pp. 897-909.e1.
    Chen Q, Hu C, Yu H, et al. 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. Clin Ther. 2019;41(5):897-909.e1.
    Chen, Q., Hu, C., Yu, H., Shen, K., Assam, P. N., Gillen, M., ... Dorinsky, P. (2019). 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. Clinical Therapeutics, 41(5), pp. 897-909.e1. doi:10.1016/j.clinthera.2019.03.007.
    Chen Q, et al. 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. Clin Ther. 2019;41(5):897-909.e1. PubMed PMID: 30982547.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. AU - Chen,Qian, AU - Hu,Chaoying, AU - Yu,Hui, AU - Shen,Kai, AU - Assam,Pryseley Nkouibert, AU - Gillen,Michael, AU - Liu,Yun, AU - Dorinsky,Paul, Y1 - 2019/04/11/ PY - 2018/11/27/received PY - 2019/03/01/revised PY - 2019/03/13/accepted PY - 2019/4/16/pubmed PY - 2019/4/16/medline PY - 2019/4/16/entrez KW - budesonide KW - chronic obstructive pulmonary disease KW - co-suspension delivery technology KW - formoterol fumarate KW - glycopyrrolate KW - pharmacokinetics SP - 897 EP - 909.e1 JF - Clinical therapeutics JO - Clin Ther VL - 41 IS - 5 N2 - 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 AUC0-12, Cmax, and Tmax. 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 AUC0-12 and Cmax were increased dose proportionally from BGF MDI 160/14.4/10 μg to BGF MDI 320/14.4/10 μg, respectively (single dose: AUC0-12, 811.8 vs 1748 h · pg/mL; Cmax, 224.3 vs 459.3 pg/mL; repeated dosing: AUC0-12, 1250 vs 2510 h · pg/mL; Cmax, 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC0-12 and Cmax were similar across all treatments (single dose: AUC0-12, 27.20-29.40 h · pg/mL; Cmax, 4.884-5.674 pg/mL; repeated dosing: AUC0-12, 69.49-77.08 h · pg/mL; Cmax, 11.30-13.12 pg/mL) and formoterol (single dose: AUC0-12, 46.49-53.58 h · pg/mL; Cmax 9.651-10.62 pg/mL; repeated dosing: AUC0-12, 81.94-85.32 h · pg/mL; Cmax, 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. SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/30982547/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 L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(19)30122-5 DB - PRIME DP - Unbound Medicine ER -