Effect of delivery device on systemic exposure to inhaled fluticasone propionate in children with asthma.

Inhaled corticosteroids are well established as the first choice of anti-inflammatory therapy for the prophylaxis of asthma in both adults and children. Current treatment guidelines recommend that inhaled corticosteroids should be prescribed for individuals with persistent asthma at all severity levels as long term treatment markedly reduces the frequency and severity of exacerbations. A large number of inhalation devices are used for delivery of asthma medication in children, and it is well known that choice of device is key for the amount of drug that reaches the lungs. For infants and preschool children, in whom active cooperation can be problematic, a pressurized metered dose inhaler (pMDI) used in conjunction with a spacer is usually preferred for maintenance therapy whereas from approximately 6 years onwards a dry powder inhaler (DPI) or breath-activated MDI is recommended [1]. The switch from one delivery device to another generates a possibility of either achieving subtherapeutic drug concentrations or excessive drug exposure with the risk of unwanted side effects. However, there are limited childhood studies available comparing systemic exposure of inhaled corticosteroids using different inhalation devices, and thus no clear rationale for dose selection and dose titration following switch between devices in children with asthma [2]. The objective of this single dose, randomized, double-blind, double-dummy, crossover study was to investigate the effect of delivery device on systemic exposure to fluticasone proprionate (FP) in children with asthma. Due to negligible oral bioavailability of FP and absence of pre-systemic metabolism in the lung, systemic appearance of FP following inhalation is considered equivalent to lung deposition [3]. The study was conducted at the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) clinical research unit in Copenhagen, Denmark. Children with a documented clinical history of mild asthma diagnosed according to the GINA guidelines and able to use the inhalation devices properly were included in the study. Subjects were excluded if they had changed their asthma medication, received systemic corticosteroids, had an airway infection or asthma exacerbation within 4 weeks prior to recruitment or were unable to withdraw from their controller therapy for the duration of the study. The local Ethics Committee provided formal approval of the study (KF 02–107/98, KF 12–136/99). Written informed consent to participate in the study was obtained from subjects and their parents/guardians. Systemic exposure to FP was examined in 13 children aged 12–15 years (10 males), following FP 500 μg inhaled via a DPI (Diskus®) or pMDI with spacer (Volumatic™). The FP dose delivered via pMDI plus spacer was given as two actuations of 250 μg where each puff was inhaled with 30 s of tidal breathing causing an exponential emptying of the aerosol plume. One child had parental consent withdrawn and another child was excluded for technical reasons. Blood samples (5 ml) were collected 10 min before drug administration (baseline) and 20 min, 40 min, 1, 2, 3, 4 and 6 h post-dose for determination of FP plasma concentration [4]. The FP analysis method had a calibration range of 10–1500 pg ml−1 from 0.5 ml plasma. Mean peak inspiratory flow rate obtained during inhalation from the DPI was 107 l min−1 (range 45–126). Delivery of FP 500 μg via a pMDI plus spacer compared with the DPI resulted in a 38% higher maximal plasma concentration (Cmax) (P = 0.02) and 70% higher area under the concentration–time curve (AUC(0,tlast)) (P < 0.01) (Figure ​(Figure1).1). Time to median peak plasma FP concentration (tmax) was furthermore longer with pMDI vs. DPI: 2 h vs. 1 h (P = 0.03) (Table S1 Online). Figure 1 Mean plasma concentrations of fluticasone propionate (FP) following administration of a single 500 μg dose via dry powder Inhaler (DPI) (Diskus®) and pressurized metered dose inhaler (pMDI) plus spacer (Volumatic™) in 12–15-year-old ... The higher systemic exposure after pMDI plus spacer may be due to exponential emptying of the spacer following subsequent inhalations resulting in a greater inhaled volume of the aerosol and increased lung deposition compared to DPI. With DPI, the inhaled volume of drug depends on the turbulence created by each single inhalation and increased impaction in the oropharyngeal region may be a limiting factor for lung deposition [3]. To our knowledge, no previous study has sought to titrate DPI and pMDI to deliver an equivalent lung dose in children, but results in adults have also suggested increased systemic activity with pMDI [5]. Inhaled FP follows linear pharmacokinetics in a wide dose range suggesting that the observed differences between devices will be similar for lower doses [6]. In conclusion, systemic exposure reflecting lung deposition of inhaled FP in 12–15-year-old asthmatic children was significantly higher when the dose was delivered via a pMDI plus spacer (Volumatic™) compared with a DPI (Diskus®). Therefore, we recommend that physicians and patients should be made aware that changing the device may significantly affect the lung dose and hence dose adjustment should be considered.