In vitro and clinical characterization of the valved holding chamber AeroChamber Plus® Flow-Vu® for administrating tiotropium Respimat® in 1–5-year-old children with persistent asthmatic symptoms. (April 2018)

• Record Type: Journal Article
• Authors: Wachtel, Herbert; Nagel, Mark; Engel, Michael; El Azzi, Georges; Sharma, Ashish; Suggett, Jason
• Is Part Of: Respiratory medicine. Volume 137(2018)
• Page Start: 181
• Page End: 190
• Publication Date: 2018-04
• Subjects: Children -- Asthma -- Fine particle fraction -- Respimat® Soft Mist™ Inhaler -- AeroChamber Plus® Flow-Vu® -- VHC; AE adverse event -- APSD aerodynamic particle size distribution -- DTL dose-to-lung -- EM emitted mass -- fe0–3, ss fraction of tiotropium excreted unchanged into urine between 0 and 3 h post-dose at steady state -- FPD fine particle dose -- HPLC high-performance liquid chromatography -- ICS inhaled corticosteroids -- NGI Next Generation Impactor -- PK pharmacokinetic -- SIP sample inlet port -- VHC valved holding chamber; Chest -- Diseases -- Periodicals; Chest -- Diseases -- Great Britain -- Periodicals; Respiratory organs -- Diseases -- Periodicals; Respiratory Tract Diseases -- Periodicals; Appareil respiratoire -- Maladies -- Périodiques; Thorax -- Maladies -- Périodiques; Appareil respiratoire -- Maladies -- Traitement -- Périodiques; Electronic journals; 616.2
• DOI: 10.1016/j.rmed.2018.03.010
• Languages: English
• ISSNs: 0954-6111

Abstract

Abstract: Background: When characterizing inhalation products, a comprehensive assessment including in vitro, pharmacokinetic (PK), and clinical data is required. We conducted a characterization of tiotropium Respimat ® when administered with AeroChamber Plus ® Flow-Vu ® anti-static valved holding chamber (test VHC) with face mask in 1–5-year-olds with persistent asthmatic symptoms. Methods: In vitro tiotropium dose and particle size distribution delivered into a cascade impactor were evaluated under fixed paediatric and adult flow rates between actuation and samplings. The tiotropium mass likely to reach children's lungs was assessed by tidal breathing simulations and an ADAM-III Child Model. PK exposure to tiotropium in preschool children with persistent asthmatic symptoms (using test VHC) was compared with pooled data from nine Phase 2/3 trials in older children, adolescents, and adults with symptomatic persistent asthma not using test VHC. Results: At fixed inspiratory flow rates, emitted mass and fine particle dose decreased under lower flow conditions; dose reduction was observed when Respimat ® was administered by test VHC at paediatric flow rates. In <5-year-old children, such a dose reduction is appropriate. In terms of dose per kg/body weight, in vitro -delivered dosing in children was comparable with adults. Transmission and aerosol holding properties of Respimat ® when administered with test VHC were fully sufficient for aerosol delivery to patients. At zero delay, particles <5 μm (most relevant fraction) exhibited a transfer efficacy of ≥60%. The half-time was>10 s, allowing multiple breaths. Standardized tidal inhalation resulted in an emitted mass from the test VHC of approximately one-third of labelled dose, independent of coordination and face mask use, indicating predictable tiotropium administration by test VHC with Respimat ® . Tiotropium exposure in 1–5-year-old patients using the test VHC, when adjusted by height or body surface, was comparable with that in older age groups without VHCs; no overexposure was observed. Adverse events were less frequent with tiotropium (2.5 μg, n = 20 [55.6%]; 5 μg, n = 18 [58.1%]) than placebo ( n = 25 [73.5%]). Conclusions: Our findings provide good initial evidence to suggest that tiotropium Respimat ® may be administered with AeroChamber Plus ® Flow-Vu ® VHC in 1–5-year-old patients with persistent asthmatic symptoms. To confirm the clinical efficacy and safety in these patients, additional trials are required. Clinical Trials Registry number: The trial was registered underNCT01634113 athttp://www.clinicaltrials.gov . Highlights: Young children may require valved holding chambers for inhalation of asthma therapy. In vitro delivered dose output of a chamber was up to 79% of Respimat without. Fine particle dose of tiotropium adequately transmitted by valved holding chamber. Tiotropium exposure comparable between ages when normalized for body surface area. Clinical data suggest tiotropium Respimat is well tolerated in preschool children.