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Clinical Pharmacokinetics

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Open Access 01-03-2021 | Pharmacokinetics | Original Research Article

Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease

Authors: Arthur Lo, Marie T. Borin, David L. Bourdet

Published in: Clinical Pharmacokinetics | Issue 3/2021

Abstract

Background and Objectives

Revefenacin is a lung-selective, long-acting muscarinic antagonist indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. The objectives of this analysis were to evaluate the pharmacokinetics of revefenacin and its major metabolite (THRX-195518) in patients with chronic obstructive pulmonary disease, and identify significant covariates affecting revefenacin disposition using a population pharmacokinetic approach based on plasma concentration–time data obtained after single- and repeated-dose once-daily administration in three phase II and two phase III studies.

Methods

Plasma concentrations of revefenacin and THRX-195518 following once-daily administration via nebulization at a dose levels ranging from 22–700 μg in 935 patients (488 men, 447 women; age 41–88 years) were analyzed using nonlinear mixed-effects modeling.

Results

Plasma revefenacin pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. Pharmacokinetic parameters for THRX-195518 were estimated using a sequential approach, where the concentration–time profiles were fit to a combined model. The formation of the metabolite in each subject was estimated to be a fixed fraction of the individually estimated (post-hoc) clearance rate of revefenacin. Four statistically significant covariates were identified: for revefenacin, age on apparent clearance and body weight on apparent intercompartment clearance, for THRX-195518, age on apparent clearance and body weight on the fraction of revefenacin apparent clearance that was metabolized to THRX-195518.

Conclusions

None of the identified statistically significant covariates were associated with a clinically meaningful effect on revefenacin or THRX-195518 exposure in patients with chronic obstructive pulmonary disease.

Registration

ClinicalTrials.gov identifier number NCT03064113, NCT01704404, NCT02040792, NCT02459080, and NCT02512510

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Title: Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease
Authors: Arthur Lo
Marie T. Borin
David L. Bourdet
Publication date: 01-03-2021
Publisher: Springer International Publishing
Keyword: Pharmacokinetics
Published in: Clinical Pharmacokinetics / Issue 3/2021
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-020-00938-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease

Abstract

Background and Objectives

Methods

Results

Conclusions

Registration

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background and Objectives

Methods

Results

Conclusions

Registration

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