Population Pharmacokinetic Analysis of Indacaterol/Glycopyrronium/Mometasone Furoate After Administration of Combination Therapies Using the Breezhaler
Administration, Inhalation
Adolescent
Adult
Aged
Anti-Asthmatic Agents
/ administration & dosage
Asthma
/ drug therapy
Child
Clinical Trials, Phase III as Topic
Dose-Response Relationship, Drug
Drug Combinations
Female
Glycopyrrolate
/ administration & dosage
Humans
Indans
/ administration & dosage
Male
Middle Aged
Models, Biological
Mometasone Furoate
/ administration & dosage
Nebulizers and Vaporizers
Pulmonary Disease, Chronic Obstructive
/ drug therapy
Quinolones
/ administration & dosage
Randomized Controlled Trials as Topic
Young Adult
Journal
European journal of drug metabolism and pharmacokinetics
ISSN: 2107-0180
Titre abrégé: Eur J Drug Metab Pharmacokinet
Pays: France
ID NLM: 7608491
Informations de publication
Date de publication:
Jul 2021
Jul 2021
Historique:
accepted:
23
04
2021
pubmed:
24
5
2021
medline:
17
12
2021
entrez:
23
5
2021
Statut:
ppublish
Résumé
Clinical 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. Pharmacokinetic 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. The 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. Two-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.
Sections du résumé
BACKGROUND AND OBJECTIVE
OBJECTIVE
Clinical 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.
METHODS
METHODS
Pharmacokinetic 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.
RESULTS
RESULTS
The 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.
CONCLUSION
CONCLUSIONS
Two-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.
Identifiants
pubmed: 34024035
doi: 10.1007/s13318-021-00689-x
pii: 10.1007/s13318-021-00689-x
pmc: PMC8298373
doi:
Substances chimiques
Anti-Asthmatic Agents
0
Drug Combinations
0
Indans
0
Quinolones
0
indacaterol acetate-mometasone furoate drug combination
0
indacaterol-glycopyrronium combination
0
Mometasone Furoate
04201GDN4R
Glycopyrrolate
V92SO9WP2I
Types de publication
Comparative Study
Journal Article
Meta-Analysis
Langues
eng
Sous-ensembles de citation
IM
Pagination
487-504Informations de copyright
© 2021. The Author(s).
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