Dataset Information

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects.

ABSTRACT:

Background

A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler^® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d.

Methods

This was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 ?g (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 ?g o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14.

Results

In total, 16 Japanese (median age 31 years [range 20-40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21-43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for C_max for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC_0-24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed.

Conclusion

Pharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups.

Trial registration

Japan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020.

SUBMITTER: Inoue S

PROVIDER: S-EPMC7791651 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects.

Inoue Satoru S Vaidya Soniya S Tillmann Hanns-Christian HC Sakita Yohei Y Machineni Surendra S Heudi Olivier O Furihata Kenichi K

BMC pulmonary medicine 20210107 1

<h4>Background</h4>A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler<sup>®</sup> device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d.<h4>Methods</h4>This was a single-center, open-label, 2-treatment crossover study with ...[more]

PMID: 33413291

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Project description:Background and objectiveClinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF.MethodsPharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 μg) and high-dose (150/50/160 μg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach.ResultsThe final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations.ConclusionTwo-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD.

Project description:Previous pharmacokinetic studies of the inhaled corticosteroid, fluticasone furoate (FF), and the long-acting, beta2-receptor agonist, vilanterol (VI) have been performed in relatively small populations using non-compartmental pharmacokinetic methods and censored data (due to low drug exposure relative to assay sensitivity). This paper presents a population pharmacokinetic analysis, utilizing pooled concentration-time data from clinical studies in healthy subjects and from global trials in patients with chronic obstructive pulmonary disease (COPD). The objective of this analysis was to characterize the population pharmacokinetics of FF and VI following once-daily inhalation dosing of FF/VI or the individual components (FF and VI) and to identify significant covariates that impact systemic exposure to FF and VI in this population.Population pharmacokinetic methods that maximize the likelihood of all data were developed to describe systemic exposure to FF and VI following once-daily FF/VI, FF, or VI, and to identify significant covariates that impact the pharmacokinetics. COPD patients (N = 1225 for the FF analysis and N = 1091 for the VI analysis; 94 and 93 % of total data, respectively) and healthy subjects contributed to the analysis.FF data were described by a two-compartment model with first-order absorption and elimination. The population grouping "race" was a significant covariate on inhaled clearance (CL/F). The area under the curve over 24 h (AUC0-24) for FF was higher for East Asian, Japanese, and South East Asian (average 23-30 %) and Asian Central, White Arabic, American Indian/Native Alaskan, and 'other' (10-26 %) subjects compared with White/Caucasians. VI pharmacokinetics were described by a three-compartment model with zero-order absorption and first-order elimination. Significant demographic covariates identified to affect pharmacokinetics of VI were age [on CL/F and central volume (V 1/F)], bodyweight (on CL/F), sex and smoking (on V 1/F).While significant effects of the covariates were observed in this study, the magnitude of these effects on systemic exposure is not large enough to warrant FF/VI dosage adjustment in patients with COPD.

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Dataset Information

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects.

Background

Methods

Results

Conclusion

Trial registration

Publications

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects.

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