Jason Suggett

Developing Ways to Evaluate in the Laboratory How Inhalation Devices Will Be Used by Patients and Care-Givers: The Need for Clinically Appropriate Testing

The design of methods in the pharmaceutical compendia for the laboratory-based evaluation of orally inhaled product (OIP) performance is intentionally aimed for simplicity and robustness in order to achieve the high degree of accuracy and precision required for the assurance of product quality in a regulated environment. Consequently, performance of the inhaler when used or even misused by the patient or care-giver has often not been assessed. Indeed, patient-use-based methodology has been developed in a somewhat piecemeal basis when a need has been perceived by the developing organization. There is, therefore, a lack of in-use test standardization across OIP platforms, and often important details have remained undisclosed beyond the sponsoring organization. The advent of international standards, such as ISO 20072:2009, that focus specifically on the OIP development process, together with the need to make these drug delivery devices more patient-friendly as an aid to improving compliance, is necessitating that clinically appropriate test procedures be standardized at the OIP class level. It is also important that their capabilities and limitations are well understood by stakeholders involved in the process. This article outlines how this process might take place, drawing on current examples in which significant advances in methodology have been achieved. Ideally, it is hoped that such procedures, once appropriately validated, might eventually become incorporated into the pharmacopeial literature as a resource for future inhaler developers, regulatory agencies, and clinicians seeking to understand how these devices will perform in use to augment ongoing product quality testing which is adequately served by existing methods.

Clinically Relevant In Vitro Testing of Orally Inhaled Products-Bridging the Gap Between the Lab and the Patient.

ABSTRACTCurrent pharmacopeial methods for in vitro orally inhaled product (OIP) performance testing were developed primarily to support requirements for drug product registration and quality control. In addition, separate clinical studies are undertaken in order to quantify safety and efficacy in the hands of the patient. However, both laboratory and clinical studies are time-consuming and expensive and generally do not investigate either the effects of misuse or the severity of the respiratory disease being treated. The following modifications to laboratory evaluation methodologies can be incorporated without difficulty to provide a better linkage from in vitro testing to clinical reality: (1) examine all types of OIP with patient-representative breathing profiles which represent normal inhaler operation in accordance with the instructions for use (IFU); (2) evaluate OIP misuse, prioritizing the importance of such testing on the basis of (a) probability of occurrence and (b) consequential impact in terms of drug delivery in accordance with the label claim; and (3) use age-appropriate patient-simulated face and upper airway models for the evaluation of OIPs with a facemask. Although it is not necessarily foreseen that these suggestions would form part of future routine quality control testing of inhalers, they should provide a closer approximation to the clinical setting and therefore be useful in the preparation for in vivo studies and in improving guidance for correct use.

Cost-effectiveness of the Aerobika* oscillating positive expiratory pressure device in the management of COPD exacerbations

Introduction COPD places a huge clinical and economic burden on the US health care system, with acute exacerbations representing a key driver of direct medical costs. Current treatments, although effective in reducing symptoms and limiting exacerbations, do not adequately target the underlying disease processes that drive exacerbation development. The Aerobika* oscillating positive expiratory pressure (OPEP) device has been shown in a real-world effectiveness study to lower the frequency of moderate-to-severe exacerbations during a 30-day post-exacerbation period. This study sought to determine the impact on exacerbations and costs and to determine the cost-effectiveness of the Aerobika* device. Methods Data from published literature and national fee schedules were used to model the cost-effectiveness of the Aerobika* device in patients who had experienced an exacerbation in the previous month, or a post-exacerbation care population. Exacerbation trends and the impact of the Aerobika* device on reducing exacerbation frequency were modeled using a one-year Markov model with monthly cycles and three health states: (i) no exacerbation, (ii) exacerbation, and (iii) death. Scenario analysis and one-way sensitivity analysis (OWSA) were also performed. Results When the effect of Aerobika* device was assumed to last 30 days, use of the device resulted in cost-savings (

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

553 per patient) and improved outcomes (ie, six fewer exacerbations per 100 patients per year) compared to no OPEP/positive expiratory pressure therapy. When the effect of the Aerobika* device was assumed to extend beyond the conservative 30-day time frame, the Aerobika* device remained the dominant strategy (21 fewer exacerbations per 100 patients per year; cost savings of

P279 Priming of a non-conducting valved holding chamber (vhc) may result in inconsistent medication delivery

1,952 per patient). Consistency in findings after performing OWSAs indicates the robustness of results. Conclusion The Aerobika* device is a cost-effective treatment option that provides clinical benefit and results in direct medical cost savings in a post-exacerbation care COPD population.

P278 Assessing different valved holding chambers (vhc) with facemask for delivered mass to carina with inhaled corticosteroid by pressurised metered-dose inhaler (pmdi)

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 childrens 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 under NCT01634113 at http://www.clinicaltrials.gov.

P86 In vitro and clinical characterisation of the antistatic valved holding chamber aerochamber plus® flow-vu® for administrating tiotropium respimat® in 1–5-year-old children with persistent asthmatic symptoms

Introduction and Objectives Priming VHCs with several actuations of medication before use may be an established practice to prepare the spacer before use. However this practice can have a significant influence on subsequent medication delivery. The present study set out to test the hypothesis that priming is not effective, or better than the use of anti-static materials. Methods The following VHCs, each with mouthpiece as patient interface (n=5 devices/group) were evaluated: AeroChamber Plus Flow-Vu Antistatic VHC (AC +FV AVHC); AeroChamber Plus; Volumatic…; Able Spacer 2…; Anti-Static Compact Space Chamber plus…. Each VHC was connected via a filter holder to a vacuum source operated at 28.3 L/min, evaluated with a pMDI (Flovent 125 µg, FP) and the Emitted Mass of FP (EMFP) determined by HPLC-UV assay. The following sequence of testing was conducted: 1) Test VHC immediately after removal from packaging (no pre-treatment) and evaluate EMFP following one actuation. 2) Supply two more actuations into the same VHC and evaluate EMFP (representing 3 actuations of priming).3) Deliver 17 more actuations into the same VHC and evaluate EMFP (representing priming of 20 actuations). 4) Clean VHC, then repeat part (1) (representing pre-conditioning by washing as an alternative to priming). Results The behaviour of EMFP (mean ±SD) with VHC type is summarised in figure 1. Conclusions Clinicians should be aware that priming of VHCs Results in inconsistent medication delivery, and is wasteful of medication. Abstract P279 Figure 1

Delivery of Respimat Soft Mist inhaler (SMI) from a Valved Holding Chamber (VHC)

Introduction and Objectives Laboratory evaluation of VHC-facemask add-ons is ideally undertaken simulating conditions of use. We report a study in which such devices for small child use were evaluated using an anatomical face-model and upper airway commensurate with that of a 4 year old child. Methods A number of VHCs with facemask (n=3 devices/group) were evaluated using an anatomical face-model and upper airway commensurate with that of a 4 year old child. Each VHC was prepared to manufacturer instructions, then evaluated by breathing simulator (ASL5000), mimicking a short coordination delay of 2 s followed by tidal breathing (tidal volume (Vt)=155 mL, I:E ratio=1:2, rate=25 cycles). The facemask was attached to ADAM-III small child model. The airway was coupled directly to the breathing simulator via a filter below its exit to capture drug particles that would penetrate as far as the carina in a real patient. 5-actuations of fluticasone propionate (50 µg, FP) were delivered at 30 s intervals. FP recovered from various locations in the aerosol pathway was subsequently assayed by HPLC-UV spectrophotometry. Results Distribution of recovered FP from each type of VHC is summarised in Table 1. Conclusions Significantly more FP was delivered to the model ‘carina’ from the AC Plus VHC with child mask (p<0.001), the increased mass counterbalanced by decreased retention of medication within the VHC. It is important that clinicians are aware that large differences in delivery efficiency may exist when a facemask is present. Abstract P278 Table 1 FP (mean μg±SD) recovered from VHCs indicated for small child use, simulating a 2 s coordination delay followed by tidal breathing Retention Location AeroChamber Plus Flow-Vu Pocket- Chamber Vortex Compact SpaceChamber Anti-Static A2A Spacer Volumatic Able* Spacer2 Optichamber Diamond* VHC 17.5±1.6 36.6±0.2 39.7±6.7 36.1±3.6 28.3±2.8 33.6±1.9 13.2±1.6 22.7±2.7 Facemask 1.4±0.2 1.9±0.8 1.2±0.2 0.0±0.0 0.2±0.1 0.1±0.1 0.0±0.0 3.4±0.8 Airway 1.1±0.2 0.4±0.2 0.6±0.3 0.1±0.1 0.4±0.1 0.0±0.0 0.2±0.0 0.7±0.1 Filter at ‘Carina’ 10.1± 1.0 4.0± 1.7 2.7± 1.5 2.1± 0.8 4.1± 0.9 1.5± 0.8 5.1± 0.9 5.1± 0.9

A Laboratory Assessment Into the Efficiency and Effectiveness of Different Oscillating Positive Expiratory Pressure Devices by Means of Patient Simulated Expiratory Waveforms

Introduction Characterisation of any inhalation product requires a comprehensive assessment including in vitro, pharmacokinetic (PK), and clinical Results We assessed tiotropium Respimat® administered with the AeroChamber Plus® Flow-Vu® antistatic valved holding chamber (test VHC) using in vitro, PK and clinical data in 1–5 year-olds with persistent asthmatic symptoms. Methods We evaluated tiotropium delivered into a cascade impactor under fixed paediatric flow rates with and without holding times in the test VHC. Tidal breathing simulations and an anatomically correct ADAM-III Child Model were employed to assess the tiotropium mass likely to reach the lungs of preschool children when Respimat® was administered with the test VHC. Clinical characterisation was based on a 12 week, randomised trial of once-daily tiotropium Respimat® or placebo as add-on to background therapy in 1–5 year-olds with persistent asthmatic symptoms (NCT01634113). PK data on systemic exposure to tiotropium Respimat® administered with test VHC in preschool children were compared with pooled data from older patients with symptomatic persistent asthma not using VHCs (NCT01383499/NCT01122680/NCT01233284/NCT01152450/NCT01696071/NCT00772538/NCT00776984/NCT01172808/NCT01172821). Results In vitro emitted mass decreased with lower flow conditions, indicating age-dependent dose reduction. In terms of dose per kg/body weight, delivered dosing at flow rates corresponding to preschool children was comparable to that at flow rates corresponding to older children (Table). Transmission and holding properties of tiotropium Respimat® administered by test VHC were fully sufficient for aerosol delivery of patients. Standardised tidal inhalation resulted in 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 Respimat® when used with test VHC. ADAM-III model data correlated well with standardised tidal breathing Results in terms of total mass delivered and mass delivered to filter (available to lungs). In separate clinical trials, tiotropium exposure in 1–5 year-old patients using the test VHC, adjusted by height or body surface, was comparable with that observed in older patients not using VHCs, with no overexposure. Safety of tiotropium Respimat® in 1–5 year-olds was comparable to placebo. Conclusion This study supports administration of tiotropium Respimat® with the AeroChamber Plus® Flow-Vu® VHC in 1–5 year-old children with persistent asthmatic symptoms. Abstract P86 Table 1 In vitro medication delivery through the test VHC with small/medium face masks at different flow rates and holding times Flow rate and corresponding age Mask Holding time, s Mean medication delivery through test VHC, μg/dose Body weight 50th percentile, kg Medication delivered per dose, ng/kg* 4.9 L/min (6– 12 months ) Small 0 0.85 (±0.04) 7.5–9.9 86–113 2 0.86 (±0.14) 87–115 5 0.55 (±0.16) 56–73 10 0.62 (±0.02) 63–83 8.0 L/min (2– 5 years ) Medium 0 0.74 (±0.05) 12.3–18.0 41–60 2 0.93 (±0.05) 52–76 5 0.72 (±0.07) 40–59 10 0.57 (±0.05) 32–46 12.0 L/min (>5  years) Medium 0 1.16 (±0.07) 18.0 64 2 0.96 (±0) 53 5 0.78 (±0.18) 43 10 0.61 (±0.02) 34 Data corresponding to age group 13–23 months are not available. *Inhalation of 2.5 µg tiotropium Respimat (as two actuations) in a 70 kg adult without use of the test VHC and face mask delivers approximately 2.5 µg or 36 ng/kg.

Medication delivery testing of valved holding chambers (VHCs) with facemask for infant use by means of a model infant face

Rationale: The SMI platform is used to deliver inhaled medications to treat different disease conditions and patient populations. VHCs are also used to treat the same patient populations and questions have arisen regarding the applicability of the SMI+VHC particularly in pediatric and geriatric patients. This laboratory investigation was undertaken to assist practitioners with information regarding potential drug delivery from the SMI+VHC. Methods: AeroChamber Plus® Flow-Vu® Anti-Static VHCs (AC+FV, Trudell Medical International, London, Canada) were evaluated with Spiriva®, Inspiolto® and Combivent® Respimat® SMI formulations. Measurements of fine particle mass (FPM, 0.54-3.99 µm aerodynamic diameter) were made by means of a chilled Next Generation Pharmaceutical impactor (NGI) equipped with USP inlet operated at 30 L/min. Assay for APIs recovered from components of the apparatus was undertaken by HPLC. Results: The measures of FPM (µg/actuation; mean ± SD) are summarized in the Table.1. Conclusions: The small differences in FPM between the SMI and SMI+ VHC were within the typical magnitude of method variability. Healthcare providers can have assurance that the use of the SMI with AC+FV VHC should deliver a similar FPM of API compared to the SMI alone. C