Inhaled corticosteroid delivery is markedly affected by breathing pattern and valved holding chamber model

Abstract

Background

There is a scarcity of high‐quality research on the efficient delivery of inhaled corticosteroids using valved holding chambers (VHCs) in children.

Methods

The delivered dose (DD) of fluticasone from a metered dose inhaler (pMDI) was tested using four VHCs: AeroChamber plus Flow‐Vu (AC), Babyhaler (BH), EasyChamber (EC), and Optichamber Diamond (OD). The in vitro setup included an anatomical child throat model, Next Generation Impactor, and a breathing simulator to generate tidal breathing of a four and a 6‐year‐old child, and adult type single inhalation.

Results

OD showed the lowest proportion of fluticasone trapped in the throat with all breathing patterns. AC showed similar fine particle dose (FPD) in the respirable range (1–5 µm) irrespective of the breathing pattern. For BH, the median FPD 1–5 µm was highest during adult breathing. OD and EC showed higher overall DD and higher doses in the 1–5 µm range with paediatric breathing profiles compared to adult inhalation. The median DD and FPD 1–5 µm were significantly lower with BH compared to any other VHCs during tidal breathing. Compared to EC, the FPD of the other VHCs were skewed towards <2 µm particles.

Conclusion

Fluticasone delivery is markedly affected by breathing pattern and VHC model. The observed differences in throat deposition and FPD delivered may have significant clinical implications for side effects and controlling airway inflammation. All VHCs intended for paediatric use should undergo testing using internationally recognised standardised methods incorporating clinically relevant paediatric breathing patterns.

Abbreviations

AC

AeroChamber plus Flow‐Vu

APSD

Aerodynamic Particle Size Distribution

BH

Babyhaler

DD

Delivered Dose

E

expiration

EC

EasyChamber

FPD

Fine Particle Dose, the portion of the delivered dose that consists of particles small enough to reach the lower respiratory tract, usually defined as particles with an aerodynamic diameter of 1–5 micrometres. Also referred as the respirable range

GINA

The Global Strategy for Asthma Management and Prevention

HPLC

High‐Performance Liquid Chromatography

I

inspiration

ICS

inhaled corticosteroids

NGI

Next Generation Impactor

OD

Optichamber Diamond

pMDI

pressurized Metered‐Dose Inhaler

RR

respiratory rate

V_t

tidal volume

VHC

valved holding chamber

1. INTRODUCTION

Asthma is the most common chronic disease in children requiring daily medication and the leading cause of childhood morbidity. ¹ Chronic airway inflammation is treated with inhaled corticosteroids (ICS). Fluticasone propionate (shortly fluticasone) is distinctly the most widely used ICS for children globally.

Delivering inhaled medication in preschool children is challenging due to lack of co‐operation, variable respiratory rate (RR), and low and variable tidal volume (V_t). In preschool children medication is administered by pressurised metered‐dose inhalers (pMDI). ² , ³ Valved holding chambers (VHC) play a critical role in ensuring efficient pulmonary delivery of inhaled medication in this age group. VHCs offer additional space for aerosol plume to develop, and they ease the need for coordination between actuation and inhalation from a pMDI. They also reduce oropharyngeal deposition while increasing the delivery of fine particles to the lungs. ³ , ⁴ , ⁵ , ⁶ The oropharyngeal deposition plays an important role with ICS due to their local adverse effects. Furthermore, pMDI+VHC is preferred over nebulisers and is strongly recommended in international guidelines. ³ , ⁷

The numerous VHCs available in the market differ in various aspects, such as material, aerodynamic characteristics, valve properties, shape, electrostatic characteristics, and volume. All of these factors can influence the total amount of medication that exits the device, and the dose delivered (DD) to the patient can vary significantly depending on the combination of pMDI and VHC. ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ This can have important implications for safety and clinical outcomes, especially with long term ICS therapy. The Global Strategy for Asthma Management and Prevention (GINA) states that using VHCs with lower volume (<350 ml) may be advantageus for very young children, ³ but a specific age limit is not defined. Nonetheless, larger VHCs are still widely used. ¹⁶ The optimal design and size of a VHC and whether VHCs with similar size and appearance are equally efficient in drug delivery remain unclear. Both VHCs with established market share and new devices entering the market are lacking high quality in vitro drug delivery testing with breathing patterns clinically relevant for small children.

According to international standards, the in vitro drug delivery of inhaled medication should ideally be studied with cascade impactors. A cascade impactor functions by drawing an aerosol sample through a series of progressively finer nozzles, with each stage collecting finer particles than the previous one. By doing so, cascade impactors measure the reach range and size of substance particles from the propellant aerosol source, which is referred to as the aerodynamic particle size distribution (APSD).

The APSD of the active pharmaceutical ingredient in the aerosol cloud produced by the inhaled medication plays a crucial role in drug delivery and treatment efficacy. The optimal particle size for inhaled medication to pass through mouth, pharynx and larynx to reach the lower airways lie within the range of 1–5 µm, known as the respirable range. It has also been speculated, that particles measuring 1–3 µm may achieve the greatest lung dose in small children being able to pass the narrow upper airways but large enough to provide efficient lung deposition by means of sedimentation. ¹⁷ , ¹⁸ Larger than 5 µm particles tend to remain in the upper airways or get swallowed, while particles <1 µm are believed to be exhaled. ¹⁹

Previous studies on the drug output of pMDI+VHC concerning ICS, fluticasone in particular, are negligible. There are a few studies done with cascade impactors using constant inspiratory flow of approximately 30 L/min, thus, not representing paediatric tidal breathing. ²⁰ , ²¹ Paediatric tidal breathing patterns have been used only in a single study, with a simple filter collector system missing relevant information about FPD and APSD. ¹⁴ Studies concerning the drug delivery of beclomethasone dipropionate or other corticosteroids cannot be directly applied to fluticasone. ²²

We aimed to assess the total delivered dose, throat deposition, and respirable dose of inhaled fluticasone with four different VHCs using clinically relevant paediatric breathing patterns. The findings offer novel insight into the drug delivery of long term inhaled anti‐inflammatory asthma medication for young asthmatic children.

2. MATERIALS AND METHODS

We used an in vitro setup. The VHCs were connected to an anatomical child throat model (Child Alberta Idealised Throat, Copley Scientific Limited, Nottingham, UK) with a silicone adapter. The throat model was followed by the cascade impactor system Next Generation Impactor (NGI, Copley Scientific Limited, Nottingham, UK). From the age of 3–4 years children are generally able to use VHCs without masks, ³ , ²³ thus masks were excluded from this study.

Three breathing profiles were studied. Paediatric tidal breathing was simulated by two oscillating patterns: 4‐year‐old (RR 24/min, V_t 150 ml, I/E 1.0 s/1.5 s) and 6‐year‐old (RR 24/min, V_t 220 ml, I/E 1.0 s/1.5 s). The third pattern represented an adult type of slow single inhalation for 3 s (1000 ml, I 3 s E 0 s). The parameters for average weight and height for the formulation of the breathing profiles were conducted from the Finnish growth curves. ²⁴ The equations for normal respiratory parameters provided by Motamedi‐Fakhr et al. ²⁵ were used to confirm that the parameters formulated fit the normal range of the age group at hand.

Four types of VHCs were studied: AeroChamber plus Flow‐Vu (AC), Babyhaler (BH), EasyChamber (EC), and Optichamber Diamond (OD). Details about the VHCs is presented in table S1 and figure S1. Three separate VHCs from different manufacturing lots were used for each brand. Before and in between the experiments the components of the VHCs were washed and dried according to the manufacturers’ instructions.

The fluticasone pMDI (Flixotide Evohaler 125 µg/dos, GlaxoSmithKline Inc., Evreux, France) was shaken vigorously before connecting to the test system. Immediately at actuation the breathing simulator (Breathing simulator BRS 3100, Copley Scientific Limited, Nottingham, UK) was started producing the appropriate breathing profiles. The drug was actuated to the VHC one dose at a time. After two doses of fluticasone and breathing simulations, samples were collected from the throat model and all eight stages of the NGI. Each study setting was repeated four times with each separate VHC producing a total of 972 samples.

The preparation of the test system included coating the cups of the NGI stages with a fixation solution to minimise particle bounce and re‐entrainment. The samples were collected by inserting 10 ml of solvent in the throat model and 15 ml of solvent in the NGI cups. The outlets of the throat model were covered, and the model was shaken. The cups were shaken with a gentle rocker (Copley Scientific Limited, Nottingham, UK) for 15 min. After adequate mixing 1.5 ml of each sample was collected to a smaller vial. The NGI samples were analysed by high‐performance liquid chromatography (HPLC) carried out by Emmace Consulting AB (Lund, Sweden) with the following setup: mobile phase; 96% ethanol/0.1% ammonium acetate 43/57 (vol/vol), pump flow rate; 1.5 mL/min, injection volume; 100 µL, detection wavelength; 226 nm, column; Waters XTerra RP18 3.5 µm, 50 × 4.6 mm. Validation shows linearity 0.03–32 µg/ml. The limit of quantitation (LOQ) is 0.03 µg/ml.

Statistical analysis was performed using IBM SPSS Statistics for Windows, version 29 (IBM Corp., NY, USA). Since the data was not normally distributed, to assess the differences in delivered dose of fluticasone among VHCs, the Kruskal‐Wallis test was used. To minimise the risk of Type I error associated with multiple comparisons and to maintain the overall familywise error rate below 0.05, the Bonferroni correction was applied with the adjusted significance level of p < .0083.

2.1. Role of the funding source

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

3. RESULTS

The median DD was statistically significantly lower for BH compared to the other VHCs in both paediatric tidal breathing patterns (Tables 1 and 2). As the V_t decreased, there was a statistically significant decrease in DD for BH (p = .002) and EC (p = .002), but nor for AC and OD. For the 3‐s single adult inhalation the median DD did not significantly differ between the VHCs (Table 2), however BH showed less consistent results.

Table 1.

The median delivered dose (µg) of fluticasone propionate by breathing profile with four different valved holding chambers (VHC).

Breathing profile	VHC	Min.	Max.	Median	Mean	SD
6‐year‐old Vt 220 ml, I/E 1.0 s/1.5 s	AC	28.7	80.8	66.5	64.3	14.4
	BH	13.0	60.0	28.6	31.6	15.5
	EC	64.5	86.2	81.4	78.1	7.5
	OD	53.4	92.1	70.9	71.2	10.2
4‐year‐old Vt 50 ml, I/E 1.0 s/1.5 s	AC	41.3	81.7	62.1	61.1	11.6
	BH	6.8	29.4	13.8	15.8	7.8
	EC	57.1	78.3	69.5	67.4	7.6
	OD	58.3	92.4	68.6	69.7	9.3
Adult Vt 1000 ml, I 3.0 s	AC	50.0	77.2	66.2	65.2	7.6
	BH	10.9	86.5	42.2	48.1	24.9
	EC	42.2	69.0	51.6	52.3	7.8
	OD	41.3	86.8	52.6	57.1	13.9

Abbreviations: AC, Aerochamber plus Flow‐Vu; BH, Babyhaler; EC, EasyChamber; E, expiration; I, inspiration; OD, Optichamber Diamond; V_t, tidal volume; SD, standard deviation.

Table 2.

Pairwise comparison of delivered dose across valved holding chambers.

Breathing profile	VHC pairs	Test Statistic	Std. Error	Std. Test Statistic	p value	Adj.p value*
6‐year‐old Vt 220 ml, I/E 1.0 s/1.5 s	BH‐AC	−16.67	5.72	−2.92	0.004	0.021
	BH‐OD	−21.58	5.72	−3.78	<0.001	0.001
	BH‐EC	−29.75	5.72	−5.21	<0.001	<0.001
	AC‐OD	−4.92	5.72	−0.86	0.390	1.000
	AC‐EC	−13.08	5.72	−2.30	0.022	0.132
	OD‐EC	−8.17	5.72	−1.43	0.153	0.918
4‐year‐old Vt 150 ml, I/E 1.0 s/1.5 s	BH‐AC	−19.25	5.72	−3.37	<0.001	0.005
	BH‐OD	−27.25	5.72	−4.77	<0.001	<0.001
	BH‐EC	−25.50	5.72	−4.46	<0.001	<0.001
	AC‐OD	−8.00	5.72	−1.40	0.162	0.970
	AC‐EC	−6.25	5.72	−1.09	0.274	1.000
	EC‐OD	1.75	5.72	0.31	0.759	1.000
Adult Vt 1000 ml, I 3.0 s	BH‐AC	−15.00	5.72	−2.62	0.009	0.052
	BH‐OD	−5.08	5.72	−0.89	0.374	1.000
	BH‐EC	−1.92	5.72	−0.34	0.737	1.000
	EC‐OD	3.17	5.72	0.55	0.580	1.000
	EC‐AC	13.08	5.72	2.29	0.022	0.132
	OD‐AC	9.92	5.72	1.74	0.083	0.496

Abbreviations: AC, Aerochamber plus Flow‐Vu; BH, Babyhaler; E, expiration; EC, EasyChamber; I, inspiration; OD, Optichamber Diamond; V_t, tidal volume.

^*Since the data was not normally distributed, to assess the differences in delivered dose of fluticasone among VHCs, the Kruskal‐Wallis test was used. To minimise the risk of Type I error associated with multiple comparisons the Bonferroni correction was applied.

The relative throat deposition for each breathing pattern and VHC are shown in Figure 1 and the pairwise comparison for statistical significance across the VHCs are shown in Table S2. OD showed the lowest proportion of fluticasone trapped in the throat with all breathing patters (Figure 1). BH showed low throat deposition with the tidal breathing patterns, but outstandingly high relative throat deposition with 3‐s single inhalation. Overall, the variation in the results was notable with a wide interquartile range.

Figure 1.

Throat deposition of fluticasone propionate with three different breathing patterns and four different valved holding chambers. Tidal breathing pattern of a 6‐year‐old (V_t 220 ml, RR 24/min, I/E 1.0 s/1.5 s). Tidal breathing pattern of a 4‐year‐old (V_t 150 ml, RR 24/min, I/E 1.0 s/1.5 s). Inhalation for 3 s (V_t 1000 ml, I 3 s). V_t, Tidal volume. RR, respiratory rate. I/E, inspiration/expiration. AC, Aerochamber plus Flow‐Vu. BH, Babyhaler. OD, EC, EasyChamber. Optichamber Diamond. [Color figure can be viewed at wileyonlinelibrary.com]

The FPD of fluticasone in the respirable range (1–5 µm) is presented in Figure 2 and the pairwise comparison across the VHCs is shown in Table S3. AC showed similar FPD in the 1–5 µm range irrespective of the breathing patterns. For BH, the median FPD in the respirable range was highest during 3‐s single inhalation, but there was a wide variation in the detected concentrations. On the other hand, OD and EC showed higher overall DD as well as higher doses in the 1–5 µm range with tidal breathing profiles compared to 3‐s single inhalation (Table 1, and Figure 2). The FPD of 1–5 µm particles was significantly lower with BH compared to any other VHCs using the 4‐year‐old and 6‐year‐old tidal breathing patterns.

Figure 2.

Fine particle dose in the respirable range 1–5 µm of two 125 µg doses of fluticasone propionate with three different breathing patterns and four different valved holding chambers (VHC). Tidal breathing pattern of a 6‐year‐old (V_t 220 ml, RR 24/min, I/E 1.0 s/1.5 s). Tidal breathing pattern of a 4‐year‐old (V_t 150 ml, RR 24/min, I/E 1.0 s/1.5 s). Inhalation for 3 s (V_t 1000 ml, I 3 s). V_t, Tidal volume. RR, respiratory rate. I/E, inspiration/expiration. AC, Aerochamber plus Flow‐Vu. BH, Babyhaler. OD, EC, EasyChamber. Optichamber Diamond. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3 illustrates the FPD profile for of each VHC during the three breathing patterns used. With both paediatric tidal breathing patterns, EC demonstrated the most uniform FPD within the 1–5 µm respirable range, leaving relatively low concentrations within the undesirable <1 µm range (Figure 3A, B). Compared to EC, the FPD distribution of the other VHCs are skewed towards <2 µm particles. The poor performance of BH is especially evident with the two tidal breathing patterns. For the 3‐s single inhalation, all VHCs showed remarkably similar FPD profiles including the 1–5 µm range (Figure 3C). While EC, OD, and AC delivered almost identical amounts of fluticasone, BH underperformed here as well.

Figure 3.

The amount of fluticasone propionate in the throat model and in different stages of the cascade impactor with three different breathing patterns and four different valved holding chambers (VHC). (A) Tidal breathing pattern of a 6‐year‐old (V_t 220 ml, RR 24/min, I/E 1.0 s/1.5 s). (B) Tidal breathing pattern of a 4‐year‐old (V_t 150 ml, RR 24/min, I/E 1.0 s/1.5 s). (C) Inhalation for 3 s (V_t 1000 ml, I 3 s). V_t, Tidal volume. RR, respiratory rate. I/E, inspiration/expiration. AC, Aerochamber plus Flow‐Vu. BH, Babyhaler. OD, EC, EasyChamber. Optichamber Diamond. Error bars: 95% CI. MO, Micro‐orifice. Label claim: 2 × 125 µg dos of fluticasone propionate (Flixotide Evohaler). Green box represent the desirable respirable range of 1–5 µm. The cut‐off diameters are different for the adult setup due to differences in the internal flow in the Next Generation Impactor. [Color figure can be viewed at wileyonlinelibrary.com]

4. DISCUSSION

This is the first publication to examine the APSD of fluticasone propionate under simulated paediatric tidal breathing patterns that mimic physiological conditions. Our study revealed significant variations in the ability of various VHCs to deliver fluticasone within the respirable range. We also demonstrated that results from studies utilising adult inhalation techniques cannot be applied to paediatric populations. The performance of the BH was generally poor, particularly noticeable across both paediatric tidal breathing patterns. Conversely, OD showed promising results with relatively low throat deposition, and along with EC, delivered the highest concentrations in the overall DD and specifically in the respirable range of 1–5 µm. OD and EC demonstrated better performance with tidal breathing patterns than with the 3‐s single inhalation technique. For AC, there were no significant differences in performance between the breathing patterns in the respirable range. During paediatric tidal breathing, the FPD distribution from other VHCs tended to skew towards particles smaller than 2 µm, in contrast to EC. The performance of BH and AC was highly unpredictable, even under tightly controlled conditions.

It is hypothesised that the optimal particle size within the respirable range for children is between 1 and 3 µm. ¹⁷ , ¹⁸ Our study showed that in this particle size range, BH delivered statistically significantly lower levels of ICS compared to all other tested VHCs in the 4‐year‐old breathing profile and compared to OD and EC in the 6‐year‐old breathing profile. There was no statistically significant difference between AC, OD, and EC, except in the 6‐year‐old tidal breathing profile where EC outperformed AC. The significant differences in the FPD 1–5 µm profiles for fluticasone observed could have clinically relevant implications in the respiratory tract of small children.

In the study by Finlay & Zuberbuhler, ²⁶ the FPD from the label claim ranged from 8% to 16% for beclomethasone dipropionate and 18–32% for salbutamol when tested with the same VHCs and tidal breathing patterns. This demonstrates that drug delivery should be measured specifically for each molecule and VHC combination. Using a filter collection system, Berg et al. ¹⁰ compared the DD of fluticasone administered with Babyhaler to that of budesonide with Nebuchamber and AeroChamber but did not compare fluticasone's DD across different VHCs. However, they noted significant differences in DD from various pMDI+VHC combinations. Only three studies have examined the APSD of pMDI fluticasone with VHCs, and these were conducted using constant adult‐type inhalation flow settings. ²⁰ , ²¹ , ²⁷ There is only one published study that evaluated the DD of fluticasone using five different VHCs; however, the drug was collected using a simple filter system and the FPD was not assessed. ¹⁴ Their measurements showed significant differences in the amounts of fluticasone deposited on the filters, even in the absence of facemasks.

It is important to note that with ICS, the poor performance of the VHC cannot be offset by increasing the dosage due to potential local adverse effects, including oral candidiasis. This is particularly critical in long‐term treatment for young children. Additionally, the unreliable performance of a VHC may lead to a suboptimal clinical response to ICS treatment, resulting in increased exacerbations, doctor visits, hospitalisations, and costs. Increasing the ICS dose may lead to unnecessary escalation of treatment as suggested by the GINA guideline, which could potentially be avoided by selecting the most effective VHC. ²⁸ Unlike short‐acting beta‐sympathomimetics, the dose of fluticasone cannot be adjusted based on an acute response. Given that the therapeutic range of fluticasone in children is relatively narrow, ³ understanding the effective delivered dose and throat deposition is particularly vital. While lower lung deposition would most likely decrease the bronchial effects of ICS, it is difficult to predict how this would modify the risk‐benefit ratio, and therefore, this needs to be explored through appropriate in vivo studies.

Our methods adhere to international standards for testing inhaled medication, and the breathing parameters in our study closely approximate real‐life scenarios. Children exhibit variable V_t and RR that change with growth. ²⁹ , ³⁰ As children age, their RR decreases, with median breaths per minute at <1 year being 37–44; 1–3 years being 25–38; 3–6 years being 22–26; and 6–12 years being 18–22 breaths/min. ³¹ Conversely V_t increases with age, and in the early years of life it is approximately 7–10 ml/kg of ideal body weight. ²⁹

Our results are confined to the in vitro model used and may not fully represent the true therapeutic effects of fluticasone. While in vitro studies provide valuable data, they cannot replicate the complexities of in vivo studies. For example, in vitro methods do not capture the real‐life interactions between the device and the patient. It is also crucial to recognise the difference between interpatient and intrapatient variability in lung deposition. Factors such as differences in inhalation technique and airway geometry significantly influence interpatient variability. However, for an individual patient with a consistent inhalation technique and specific airway geometry, interpatient differences are irrelevant. For such a patient, the balance between therapeutic and adverse effects is only altered by changes in the FPD delivered by the VHC. Our in vitro experiments have conclusively demonstrated that such variations in DD and FPD could arise from switching between VHCs. Our highly standardised in vitro model allowed us to evaluate DD without confounding factors such as poor cooperation, crying, and incomplete lip seal. The throat model and cascade impactor used in this study provided crucial insights into the quantity of medication trapped in the throat and the optimal APSD. Supporting our in vitro findings, clinical trials have also observed significant differences in lung bioavailability depending upon the VHC used. ²⁸ Previous studies also seem to suggest that differences in the respirable drug mass in vitro would equate to similar differences in vivo lung deposition. ³² , ³³

Our analysis highlights the variability in VHCs and underscores its substantial implications for policy formulation, implementation, and the delivery of care to the considerable number of children dependent on inhaled asthma medications. Despite the in vitro evidence demonstrating the superior drug delivery of smaller VHCs, the continued use of larger variants appears unjustifiable. It is critical to recognise that different types of VHCs are not necessarily interchangeable, even if they appear similar in volume and design. In addition, the tidal breathing patterns of small children likely play a crucial role in the effective delivery of inhaled fluticasone propionate. While further in vivo trials are essential to ascertain the clinical impact of these differences, the influence of VHCs on drug delivery can no longer be ignored. All VHCs currently in the market should undergo testing using internationally recognised, standardised methods for DD and APSD, incorporating clinically relevant breathing patterns. Regulatory authorities should limit the approval and availability of VHCs that either demonstrate inadequate drug delivery or lack comprehensive testing.

KEY MESSAGE

Our study is the first to demonstrate significant differences in the ability of VHCs to deliver inhaled fluticasone propionate within the respirable range using physiologically relevant paediatric tidal breathing patterns. We also found that results from studies using adult inhalation techniques, such as single steady inhalation flow, cannot be applied to the paediatric population. The observed differences in throat deposition and fine particle dose delivery of ICS may have important clinical implications for reducing side effects and effectively controlling airway inflammation.

It has been 70 years since the introduction of the first spacer device, yet the treatment of our most vulnerable patient group—children—still relies heavily on data extrapolated from adult studies. Our results underscore the pressing need for high‐quality, child‐specific research to ensure that our younger population receives the most effective care possible. While further in vivo trials are essential to ascertain the clinical impact of these differences, the influence of VHCs on drug delivery cannot be overlooked. Global guidelines should align to recommend that VHCs intended for the treatment of children should undergo testing using internationally recognised standardised methods that incorporate clinically relevant paediatric breathing patterns. Regulatory authorities should limit the approval and availability of VHCs that either demonstrate inadequate drug delivery or lack comprehensive testing.

AUTHOR CONTRIBUTIONS

Laura Ojanperä: Conceptualisation; Investigation; Writing—original draft; Methodology; Validation; Visualisation; Writing—review and editing; Software; Formal analysis; Data curation. Lauri Lehtimäki: Conceptualisation; Methodology; Validation; Writing—review and editing; Data curation; Supervision. Heini Huhtala: Writing—review and editing; Writing—original draft; Validation; Methodology; Software; Formal analysis; Data curation. Péter Csonka: Conceptualisation; Investigation; Funding acquisition; Writing—original draft; Methodology; Validation; Visualisation; Writing—review and editing; Project administration; Formal analysis; Software; Data curation; Supervision; Resources.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

Supporting information

Supporting information.

Ojanperä L, Lehtimäki L, Huhtala H, Csonka P. Inhaled corticosteroid delivery is markedly affected by breathing pattern and valved holding chamber model. Pediatr Pulmonol. 2025;60:e27300. 10.1002/ppul.27300

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Data collected for the study, along with a data dictionary defining each field in the set, will be made available 1 year after publication, pending approval of a proposal and a signed data access agreement. All data requests should be submitted to the corresponding author for consideration.