Effect of AeroChamber Plus™ on the lung and systemic bioavailability of beclometasone dipropionate/formoterol pMDI

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Use of a spacer minimizes oropharyngeal deposition and optimizes drug targeting to the airways in subjects with coordination difficulties. However, the increase in pulmonary deposition often observed with spacer devices, could potentially lead to an increase in overall systemic exposure.• EMA guidelines recommend that the development of a pMDI should always include testing of at least one specific spacer for use with a particular pMDI.• The aim of this study was to examine the effect of AeroChamber Plus™ on the lung bioavailability and total systemic exposure of a hydrofluoroalkane (HFA) pMDI fixed combination of extra‐fine beclometasone dipropionate/formoterol (100/6 µg) (Foster®).WHAT THIS STUDY ADDS• The use of AeroChamber Plus™ optimizes the lung delivery of beclometasone and formoterol in subjects that find it difficult to synchronize aerosol actuation with the inspiration of breath.• The total systemic exposure of beclometasone 17‐monopropionate and formoterol was not significantly increased by the use of the AeroChamber Plus™ spacer.• Use of the AeroChamber Plus™ spacer device with the extra‐fine beclometasone dipropionate/formoterol (100/6 µg) fixed combination pMDI can be a valuable option for certain patients groups, such as subjects with difficulties in achieving an adequate inhalation technique.AIM To assess the effect of AeroChamber Plus™ on lung deposition and systemic exposure to extra‐fine beclometasone dipropionate (BDP)/formoterol (100/6 µg) pMDI (Foster®). The lung deposition of the components of the combination given with the pMDI was also evaluated using the charcoal block technique.METHODS Twelve healthy male volunteers received four inhalations of extra‐fine BDP/formoterol (100/6 µg) using (i) pMDI alone, (ii) pMDI and AeroChamber Plus™ and (iii) pMDI and charcoal ingestion.RESULTS Compared with pMDI alone, use of AeroChamber Plus™ increased the peak plasma concentrations (Cmax) of BDP (2822.3 ± 1449.9 vs. 5454.9 ± 3197.1 pg ml−1), its active metabolite beclometasone 17‐monopropionate (17‐BMP) (771.6 ± 288.7 vs. 1138.9 ± 495.6 pg ml−1) and formoterol (38.4 ± 17.8 vs. 54.7 ± 20.0 pg ml−1). For 17‐BMP and formoterol, the AUC(0,30 min), indicative of lung deposition, was increased in the AeroChamber Plus™ group by 41% and 45%, respectively. This increase was mainly observed in subjects with inadequate inhalation technique. However, use of AeroChamber Plus™ did not increase the total systemic exposure to 17‐BMP and formoterol. Results after ingestion of charcoal confirmed that AUC(0,30 min) can be taken as an index of lung bioavailability and that more than 30% of the inhaled dose of extra‐fine BDP/formoterol 100/6 µg was delivered to the lung using the pMDI alone.CONCLUSIONS The use of AeroChamber Plus™ optimizes the delivery of BDP and formoterol to the lung in subjects with inadequate inhalation technique. The total systemic exposure was not increased, supporting the safety of extra‐fine BDP/formoterol pMDI with AeroChamber Plus™.

Pharmacokinetics and pharmacodynamics of an extrafine fixed pMDI combination of beclometasone dipropionate/formoterol fumarate in adolescent asthma

“…Since the absorption by gastro‐intestinal route is much slower than the absorption by the lung ( t max at approximately 4 h and 2 h for formoterol and B17MP, respectively ), it is reasonable to assume that the amount of drug reaching the blood in the first 30 min after inhalation is predominantly coming from the lungs. In fact in a study on healthy volunteers, the systemic exposures at early time points (AUC(0,0.5 h)) after BDP/FF pMDI administration were not affected by prevention of gastrointestinal absorption with charcoal block , demonstrating that this parameter is a valid indicator of pulmonary absorption and lung deposition. In view of these considerations, it was notable that BDP/FF pMDI in adolescents was not higher and not significantly different to BDP/FF pMDI in adults in terms of AUC(0,0.5 h) for both B17MP and formoterol (90% CI 0.63, 1.13).…”

“…The point estimates (PE) and 90% confidence intervals (CI) of the geometric mean ratio fixed/free were 0.92 (90% CI 0.82,1.03) and 0.95 (90% CI 0.86, 1.05) for B17MP and formoterol, respectively (Tables and ). The systemic exposures at early time points assessed as index of pulmonary absorption (AUC(0,0.5 h)) for the fixed combination was 18% (90% CI 0.64, 1.05) and 3% (90% CI 0.74, 1.20) lower than for the free combination, for B17MP and formoterol, respectively (Tables and ). Peak concentration ( C max ) for the fixed combination was 16% (90% CI 0.70, 1.01) lower for B17MP while it was equivalent to the free combination for formoterol (90% CI 0.82, 1.22) (Tables and ).…”

“…An additional analysis was performed by stratifying adolescents into two groups of patients based on their AUC(0,0.5 h) for B17MP and formoterol for the free and the fixed combination without VHC device. AUC(0,0.5 h) is an index of pulmonary absorption and therefore patients having a low degree of coordination between actuation and inhalation are expected to have lower AUC(0,0.5 h) without the use of the VHC. Therefore, patients with AUC(0,0.5 h) below the 50th percentile were classified as ‘poor’ coordinators and those with AUC(0,0.5 h) above the 50th percentile were classified as ‘good’ coordinators.…”

“…In fact in a study on healthy volunteers, the Figure 5 AUC(0,0.5 h) (index of pulmonary absorption) (95% confidence intervals) for formoterol and B17MP following inhalation of the extrafine fixed (BDP/FF pMDI) combination (A) and following inhalation of the extrafine fixed combination (BDP/FF pMDI) with VHC (B), in two groups of asthmatic adolescents: patients with poor inhalation technique (low50th percentile) and patients with good inhalation technique (high 50th percentile). Differences were considered significant at P < 0.05; **** , P < 0.0001; NS, not significant systemic exposures at early time points (AUC(0,0.5 h)) after BDP/FF pMDI administration were not affected by prevention of gastrointestinal absorption with charcoal block [18], demonstrating that this parameter is a valid indicator of pulmonary absorption and lung deposition. In view of these considerations, it was notable that BDP/FF pMDI in adolescents was not higher and not significantly different to BDP/FF pMDI in adults in terms of AUC(0,0.5 h) for both B17MP and formoterol (90% CI 0.63, 1.13).…”

“…The point estimates (PE) and 90% confidence intervals (CI) of the geometric mean ratio fixed/free were 0.92 (90% CI 0.82,1.03) and 0.95 (90% CI 0.86, 1.05) for B17MP and formoterol, respectively (Tables 3 and 5). The systemic exposures at early time points assessed as index of pulmonary absorption (AUC(0,0.5 h)) [18] for the fixed combination was 18% (90% CI 0.64, 1.05) and 3% (90% CI 0.74, 1.20) Values are arithmetic mean (SD), except median (range) for t max . *One patient was excluded from the PK analysis due to quantifiable concentrations of B17MP at pre-dose > 5% C max [11] (Tables 3 and 5).…”