The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holding chamber is independent of age and body size

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Abstract

Background

Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combination with a valved holding chamber (VHC) to overcome the problem of coordinating inhalation with actuation. However, the influence of age and body size on the systemic exposure of drugs to be administered via a pMDI with VHC is still not fully elucidated. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed combination of beclometasone-dipropionate/formoterol-fumarate administered via pMDI with VHC in children, adolescents and adults.

Methods

The pharmacokinetics of formoterol and beclometasone-17-monopropionate (active metabolite of beclometasone-dipropionate) was evaluated over 8 h from three studies, each performed in a different age and body size group. Children (7–11 years, n = 20), adolescents (12–17 years, n = 29) and adults (≥18 years, n = 24) received a single dose of beclometasone/formoterol (children: 200 μg/24 μg, adolescents and adults: 400 μg/24 μg) via pMDI with AeroChamber Plus™.

Results

The systemic exposure in children in comparison to adolescents was equivalent for formoterol while it was halved for beclometasone-17-monopropionate in accordance with the halved dose of beclometasone administered in children (90% CIs within 0.8–1.25 for formoterol and 0.4–0.625 for beclometasone-17-monopropionate). The systemic exposure to beclometasone-17-monopropionate and formoterol was equivalent between adolescents and adults.

Conclusions

The systemic exposure to the active ingredients of a fixed dose combination of beclometasone/formoterol administered via pMDI with AeroChamber Plus™ correlates with the nominal dose independently of patient age and body size. Thus, dose reduction in relation to age when using a pMDI with VHC may be unnecessary for reducing the systemic exposure in children.

Introduction

International guidelines for treatment of childhood asthma such as GINA [1] recommend prescription of inhaled corticosteroids adjusted to age or body size [2], [3], [4], [5]. The deposition of drug in the lungs determines the clinical response, whereas systemic exposure in terms of drug concentration in the bloodstream determines the risk of systemic side effects. Children in comparison to adolescents and adults under the same anti-asthmatics dose regimen may be exposed to significantly higher systemic concentrations due to their lower body size. Thus, the rationale behind age and body size dose adjustment is to reduce the systemic exposure and minimize the risk of unwanted side effects in children. However, the influence of age and body size on the systemic exposure is not yet fully elucidated.

An extra-fine hydrofluoroalkane (HFA) fixed pressurized metered-dose inhaler (pMDI) combination of beclometasone dipropionate (BDP)/formoterol fumarate (FF) is licensed for use in asthmatic adults and currently under development in the pediatric population. In children, pMDIs are recommended to be used in combination with valved holding chambers (VHCs) to avoid the problem of coordinating inspiration with actuation. VHCs maximize lung deposition and minimize the extra-thoracic delivery of drug. In a recent scintigraphic study [6] in which a FF pMDI formulation [7] with the same composition of BDP/FF pMDI [8] was used in conjunction with AeroChamber Plus™, the extra-thoracic drug delivery was minimized to less than 10% of the total nominal dose. Considering that only a fraction (oral systemic availability [6], [9], [10]) of the extra-thoracic component contributes to the total blood levels, the systemic exposure to beclometasone-17-monopropionate (B17MP; active metabolite of BDP) and formoterol after inhalation via BDP/FF pMDI with AeroChamber Plus™ can be considered a reasonable indicator of lung deposition.

Debate remains regarding the safety of long-term use of inhaled corticosteroids/long acting β2-agonists (ICS/LABA) in children [11], [12], [13]. Concerns primarily arose from short-term studies showing reduced lower leg growth rate and impact on the hypothalamic-pituitary-adrenal axis after using ICS [14]. The clinical relevance of these findings is still unknown, but a recent large randomized controlled study of 943 children with asthma demonstrated a lower mean adult height of 1.2 cm in the budesonide treated children compared to placebo [15]. Therefore, prescription of ICS to children have been recommended at lower nominal doses of that recommended in adults [1], [2], [4].

In a previous study we found similar systemic exposure to a fixed nominal dose of budesonide delivered via a pMDI with VHC in children and adults [16]. This suggests that dose-reduction in relation to age may lead to significantly lower systemic exposures in young patients, possibly reflecting a lower and sub-therapeutic lung dose. In the present study, we have again investigated the influence of age and body size on the systemic exposure from an ICS/LABA fixed combination inhaled via pMDI with VHC. We studied the systemic exposures to formoterol and B17MP after a single dose administration of BDP/FF pMDI used with AeroChamber Plus™. In order to disentangle the effects of age and body size, we studied three different asthma populations: (1) children aged 7–11 years, (2) adolescents aged 12–17 years, and (3) adults aged ≥18 years.

Section snippets

In vitro study data

An Andersen Cascade Impactor (ACI) (Copley Instruments, Nottingham, UK) operated at 28.3 l/min was used to determine the particle size distributions of the pMDI with VHC used in the study at two different dose strengths of BDP/FF (100/6 μg and 50/6 μg per actuation). Devices were actuated directly into the induction port of the impactor and the amount of drug collected at each stage was determined using a high performance liquid chromatography with U.V. detector fully validated method. The

In vitro results

The in vitro deposition parameters of BDP and FF for the different strengths of BDP/FF pMDI used in combination with AeroChamber Plus™ are shown in Table 1. The total emitted dose matched with the nominal dose of BDP and FF for both strengths. According to the nominal doses, the delivered dose (total emitted dose subtracted by the amount of drug recovered in the actuator and VHC) and the fine particle dose (particles of the delivered dose <4.7 μm) of BDP was halved for BDP/FF 50/6 μg pMDI in

Main finding

The systemic exposure to B17MP (active metabolite of BDP) and formoterol after BDP/FF pMDI administration with AeroChamber Plus™ was independent of age and body size. The same dose of FF administered through the pMDI with VHC in children, adolescents and adults led to comparable systemic exposures in the three populations. For BDP, children received half the dosage of adolescents and adults which led to a corresponding reduction in the systemic levels of B17MP to half of that recorded in

Contributions

All authors contributed to study design conceptualization, analysis and interpretation, and manuscript preparation and/or critical revision.

Competing interests

This study was financially supported by Chiesi Farmaceutici S.p.A; Mirco Govoni, Annalisa Piccinno, Germano Lucci, Gianluigi Poli, Roberta Baronio and Daniela Acerbi are employed at Chiesi Farmaceutici S.p.A that sponsored the clinical trials in children, adolescents and adults. Dave Singh was the principal investigator of the trial in adults and received sponsorship to attend international meetings, honoraria for lecturing or attending advisory boards and research grants from Chiesi. Piotr

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