Model‐based evaluation of pulmonary pharmacokinetics in asthmatic and COPD patients after oral olodaterol inhalation

Abstract

AIMSOlodaterol is an orally inhaled β 2 -agonist for treatment of chronic obstructive pulmonary disease (COPD). The aims of this population pharmacokinetic (PK) analysis were: (1) to investigate systemic PK and thereby make inferences about pulmonary PK in asthmatic patients, COPD patients and healthy volunteers, and (2) to assess whether differences in pulmonary efficacy might be expected based on pulmonary PK characteristics. METHODSPlasma and urine data after olodaterol inhalation were available from six clinical trials comprising 710 patients and healthy volunteers (single and multiple dosing). To investigate the relevance of covariates, full fixed-effect modelling was applied based on a previously developed healthy volunteer systemic disposition model. RESULTSA pulmonary model with three parallel absorption processes best described PK after inhalation in patients. The pulmonary bioavailable fraction (PBIO) was 48.7% (46.1-51.3%, 95% confidence interval) in asthma, and 53.6% (51.1-56.2%) in COPD. In asthma 87.2% (85.4-88.8%) of PBIO was slowly absorbed with an absorption half-life of 18.5 h (16.3-21.4 h), whereas in COPD 80.1% (78.0-82.2%) was absorbed with a half-life of 37.8 h (31.1-47.8 h). In healthy volunteers absorption was faster, with a half-life of 18.5 h (16.3-21.4 h) of the slowest absorbed process, which characterized 74.6% (69.1-80.2%) of PBIO. CONCLUSIONSThe modelling approach successfully described data after olodaterol inhalation in patients and healthy volunteers. Slow pulmonary absorption was demonstrated both in asthma and COPD. Absorption characteristics after olodaterol inhalation indicated even more beneficial lung targeting in patients compared to healthy volunteers. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• A long pulmonary residence time was demonstrated in healthy volunteers that might contribute to the long-lasting pulmonary efficacy of olodaterol inhaled with the Respimat® device. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2016) 82 739-753 739

Inhaled Therapy in Respiratory Disease: The Complex Interplay of Pulmonary Kinetic Processes

“…Three PK and/or PD examples, namely, (1) albuterol, (2) fluticasone propionate/budesonide, and (3) olodaterol, will be discussed in detail below [ 81 – 85 ]. Further PK evaluations have also been published for inhaled drugs such as glycopyrronium [ 61 ], a LAMA, and AZD5423, a nonsteroidal glucocorticoid receptor modulator [ 86 ].…”

“…This could lead to a higher fraction of the drug to be cleared by the mucociliary clearance in patients compared with healthy volunteers, and consequently, a lower fraction of deposited drug being absorbed in the lung. For bronchodilating drugs or quickly dissolving corticosteroids, as in this case budesonide, the difference in pulmonary PK and resulting systemic concentrations is less pronounced [ 82 , 85 ]. These drugs dissolve faster in the lung fluids compared with fluticasone propionate and might, therefore, already be absorbed to the pulmonary tissue before a substantial amount of particles can be cleared by the mucociliary clearance.…”

“…The impact of asthma and COPD on the pulmonary PK characteristics of olodaterol was evaluated in a population PK analysis. Here, despite the decreased lung function in asthma and COPD patients, pulmonary bioavailable fractions of inhaled olodaterol were comparable with healthy volunteers [ 85 ]. Although this result is consistent with the established lung dose for the soft mist inhaler used [ 92 ], overall pulmonary absorption was slower in patients [ 85 ].…”

“…Here, despite the decreased lung function in asthma and COPD patients, pulmonary bioavailable fractions of inhaled olodaterol were comparable with healthy volunteers [ 85 ]. Although this result is consistent with the established lung dose for the soft mist inhaler used [ 92 ], overall pulmonary absorption was slower in patients [ 85 ]. This is unexpected given that airway epithelia are typically damaged in asthma patients [ 93 ], and the integrity of tight junctions is compromised in COPD patients [ 94 ].…”

Advances in experimental and mechanistic computational models to understand pulmonary exposure to inhaled drugs

“…Unlike empirical population-based modelling, which can be used to analyse and interpret the clinical pharmacokinetics of inhaled drugs (Borghard et al 2016a; Borghardt et al 2016b; Bartels et al 2013), mechanistic modelling requires identification of each key step leading up to and controlling rate and extent of absorptive clearance, as well as an understanding of the local and systemic tissue interactions (Borghardt et al 2015). These mechanism-based models are deterministic, but semi empirical in that they rely on robust quantitative data characterizing each of these key processes (Korzekwa et al, 2017).…”