INTRODUCTION

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Aerosolized drugs are prescribed in doses adjusted to age or body weight according to contemporary guidelines for asthma management (1). This aims to provide similar drug concentrations in patients of different ages and is based on the assumption that a fixed fraction of the prescribed dose of aerosol reaches the lungs irrespective of age. However, for anatomical and physiological reasons it is more likely that the lung deposition is age dependent.

Drug concentration in the lungs is relevant for the clinical effect, whereas drug concentration in the circulation determines the risk of systemic side effects (2, 3). Safety is therefore the main reason for dose reduction in children. In the present study, we chose to study the effect of age on the plasma concentration of budesonide from an inhaled aerosol delivered from a pressurized metered dose inhaler (pMDI) with spacer (Nebuchamber).

	METHODS

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Patients

Outpatients with a history of asthma in a stable condition were sought among children aged 2-3 and 4-6 yr and adults older than 18 yr. Before entering the study, the patients had to demonstrate correct and efficient inhalation techniques with a pMDI fitted with Nebuchamber. The patients gave their written informed consent to participate in the study. For a child, this was obtained from a parent or legal guardian. The child gave a verbal assent. The Danish National Board of Health and the Ethics Committee of Copenhagen approved the study.

Study Design

The study was of an open design. The inhalation technique was monitored and trained. Any budesonide treatment was stopped 2 d before the study day. Budesonide inhalations were administered and blood samples were taken at scheduled time points for 8 h.

Study Methods

Budesonide (Pulmicort; AstraZeneca R&D, Lund, Sweden) was administered in the morning as a suspension aerosol via a pMDI and a 250-ml steel spacer with a two-way valve with less than 2 ml dead space (Nebuchamber; AstraZeneca, Lund, Sweden). The 2- to 3-yr-old children used the facemask provided with the spacer wheres the older patients inhaled through the mouthpiece with a noseclip applied. Each patient had an individual inhaler and spacer. The pMDI was primed before inhalation by firing 10 puffs into a plastic bag using a separate adapter. The pMDI was shaken thoroughly immediately before each actuation. A total nominal dose of 400 µg was administered as two separate doses of 200 µg with an interval of 45 s. The patients were instructed to inhale each dose from the spacer using slow tidal breathing for 30 s.

After drug inhalation, the patients rinsed their mouths with 2 × 10 ml of water. This was not possible in young children. Children who used a facemask had their face wiped with an ethanol-moistened tissue in order to recover any budesonide deposited on the facial skin covered by the facemask during drug administration.

Budesonide was recovered from spacers, mouthpieces, or facemasks, and facial tissues by ethanol. Budesonide content in equipment and mouth rinses was determined by liquid chromatography.

The dose to patient was calculated as the delivered dose of the batch measured in vitro from the pMDI with adapter, after subtraction of the drug recovered from the equipment, facial tissues, and mouth rinses.

Before and at 20, 40, 60 min and at 2, 3, 4, 6, and 8 h after start of drug administration, blood samples (5 ml) for determination of total budesonide in plasma were obtained from an indwelling catheter (Venflon 2 0.8/25 mm; Ohmeda AB, Helsingborg, Sweden) inserted into a forearm vein. At each sampling the first milliliter of blood was discarded, and after collection of the sample, the catheter was flushed with 2 ml heparinized saline (10 IU/ml) to keep it patent. Li-heparinized (Venoject) glass tubes were used for sample collection. The tubes were turned upside down at least eight times and then immediately centrifuged at 1,300 × g for 10 min. The plasma was transferred to a polystyrene tube and immediately frozen at 20° C until analysis. Budesonide (free and bound) was isolated from plasma by solid phase extraction and analyzed by liquid chromatography plus tandem mass spectrometry with atmospheric pressure chemical ionization. The lower limit of quantification (LOQ) was 25 pmol/L with a coefficient of variation of 24% over the analytical period.

Statistical Analysis

Pharmacokinetic parameters were estimated with standard, nonparametric methods. The area under the curve of plasma concentration versus time (AUC) was calculated by the trapezoidal rule up to the last measured plasma concentration above or equal to the lower LOQ, using the actual measurement times. The terminal elimination rate k_el was calculated for each individual from the plasma concentration data by selecting a number of points on which the ln C(t) versus t curve was approximately linear and then doing a linear regression. The terminal half-life was then calculated as ln 2/k_el. C_max denotes the maximum plasma concentration and T_max denotes the corresponding (actual) time point. C₂₀ denotes the plasma concentration at 20 min, that is, in the first sample. The individual AUC, C_max, C₂₀, and T_1/2 data were log transformed before analysis. The results are then expressed as geometric means. The pharmacokinetic parameters were compared between age classes with an analysis of variance model with age class as the only factor.

	RESULTS

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Thirty patients were enrolled in the study and 26 patients completed the study. Three children (two of 3 yr and one of 5 yr) were excluded due to difficulties in blood sampling and one adult withdrew for personal reasons. No adverse events were reported during the study. Eight children aged 2-3 yr (mean = 2.5 yr), 8 children aged 4-6 yr (mean = 5.1 yr), and 10 adults (mean = 31.8 yr) completed the study. The mean delivered dose from the inhalers was 183 µg/actuation (CV = 4.1%), that is, the mean total treatment dose was 366 µg. The average dose to patient was 230 µg (range 141-285 µg), that is, 58% of the nominal dose and 63% of the delivered dose.

Plasma concentration of budesonide was below the lower LOQ in all samples taken before drug inhalation. C_max had already been reached at the first sampling point (C₂₀) in 24 of 26 patients; therefore, in some patients, C_max may have been underestimated and T_max may have been overestimated. No significant difference was found between the three age groups for dose to patient (p = 0.45), AUC (p = 0.43), or T_1/2 (p = 0.35). C₂₀ differed significantly between children and adults. Results are summarized in Tables 1 and 2. Individual values of dose to patient, AUC, and T_1/2 are plotted in Figures 1, 2, and 3; mean plasma concentration profiles for the three age groups are shown in Figure 4.

View larger version (67K): [in this window] [in a new window]   Figure 1.   Dose to patient: mean and individual values in the three age groups.

View larger version (49K): [in this window] [in a new window]   Figure 2.   AUC: mean and individual values in the three age groups.

View larger version (52K): [in this window] [in a new window]   Figure 3.   T1/2: mean and individual values in the three age-groups.

View larger version (12K): [in this window] [in a new window]   Figure 4.   Mean plasma concentration of budesonide versus time in the three age groups.

	DISCUSSION

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We found that the systemic exposure (pl-concentration) of budesonide inhaled from a pMDI with a Nebuchamber spacer was similar in young children and adults inhaling a fixed dose, that is, the systemic dose increased proportionally with age. This suggests that from a safety perspective the prescribed dose should not need to be adjusted for age.

The dose to patient, reflecting the amount of drug that is available for inhalation, was similar in young children and adults. This is compatible with previous studies on dose to patient in young children using the Nebuchamber metal spacer (4, 5). Other spacers have different characteristics and may provide an age-related dose to patient (5). Therefore, the implications of the present study cannot be extrapolated to other devices where dose to patient may be influenced by the age of the patient. Unexpectedly, the systemic exposure (pl-concentration) of budesonide was also similar in the three age groups as reflected in similar AUC and T_1/2. If similar fractions of the fixed dose provided from the spacer had reached the lungs in adults as in young children, the plasma concentration would be increased in the young children as compared with adults. As the plasma concentration was similar, the systemic dose must have been increased in adults as compared with young children.

AUC reflects the drug concentration in the circulation over time and T_1/2 reflects the rate of drug elimination. C₂₀ was significantly higher in children than in adults, probably reflecting a more rapid rate of absorption in children, a general phenomenon previously described (6): the systemic dose of budesonide is mainly attributed to the lung dose. Budesonide inhaled to the lungs is not metabolized in the lung tissue, and is rapidly absorbed to the bloodstream bypassing the liver, thus providing complete systemic bioavailability. The absorption of budesonide from the buccal mucosa and the pharynx is negligible, and budesonide deposited in the mouth and pharynx will be swallowed and absorbed from the gastrointestinal tract, where it undergoes extensive first pass metabolism in the liver (7). Therefore the increased systemic dose in young children and adults reflects that lung dose increases with age. However, the absolute lung dose cannot be estimated as the exact gastrointestinal contribution is unknown. The gastrointestinal contribution to the systemic dose after inhalation from a large volume spacer (Nebuhaler) has been found to be negligible in a study in healthy adults (8), whereas it was estimated to account for about 20% of the total systemic dose in school-age children using Turbohaler (9). The gastrointestinal contribution to the systemic dose depends on the first-pass metabolism, which seems to differ with age (10). Because the first-pass metabolism of budesonide was not determined in the present study, we cannot estimate lung dose. Furthermore, the oral dose was minimized in adults by mouth rinsing, but this was not possible in young children. This added contribution to the systemic dose from the oral dose in young but not in older patients would tend to overestimate the lung dose in young children. This bias actually accentuates the finding that the lung dose is reduced in young children.

Increasing upper airway geometry may explain the increased amount of aerosol penetrating into the lower airways of adults. This interpretation is supported in an in vitro study showing that an increased mass of fine particle aerosol passes through the cast of the upper airway of an adult as compared with the cast of the upper airway of a child (11).

Lung deposition in children of different ages has been reported in five previous studies. Lung deposition from a pMDI with spacer (Babyhaler + mouthpiece) in a study of eight children 5-9 yr old correlated with age (r = 0.77, p = 0.03) (12). Similarly, lung deposition from pMDI and spacer (Aerochamber + facemask) in 15 young children 3-60 mo old correlated with age (r = 0.56, p = 0.03) and weight (r = 0.68, p = 0.005) (13). Both studies estimated lung deposition with gamma scintigraphy.

Lung deposition estimated by gamma scintigraphy from a dry powder inhaler, Turbuhaler, in 23 children with asthma aged 6 to 16 yr correlated with age (r = 0.53, p = 0.009), height (r = 0.57, p = 0.005), and peak inspiratory flow (PIF) (r = 0.54, p = 0.008) (14). The latter finding may have been biased by flow dependency of Turbuhaler reducing the dose to patient in younger children (15). Still, no correlation was observed between lung dose and PIF for children with PIF above 55 L/min (n = 18, r = 0.10, p = 0.70), whereas the correlation between lung dose and age was also significant (r = 0.48, p = 0.04) for these children.

Lung deposition from a Turret nebulizer, as determined by gamma scintigraphy, was 1.1% of delivered dose in 12 infants aged 0.3 to 1.4 yr versus 2.7% in 8 schoolchildren (6.3-18.0 yr) (95% CI for the difference between the two age groups: 1.0; 2.4) (16).

The systemic dose in 10 young children aged 3-6 yr inhaling budesonide from a Pari LC Plus nebulizer was 6% of nominal dose (17). In an adult study using the same nebulizer the systemic availability was 15% (18). In the latter study, a dosimetric technique was applied that could account for some of the increased lung dose.

The overall conclusion from the available evidence suggests that lung dose is age dependent, and therefore the systemic exposure (pl-concentration) of an inhaled aerosol is independent of age. This suggests that from a safety perspective similar nominal doses can be prescribed irrespective of age.

The sensitivity to steroids may be age dependent, but separate studies of systemic budesonide activity, through measurements of 20-h plasma cortisol, suggest that the systemic sensitivity to steroids is not higher in children than in adults (19, 20).

Because dose to patient is constant with age and lung dose seems to increase with age, the local deposition of budesonide in the mouth and pharynx is inversely related to age. This corresponds with previous in vitro findings (11). Although local side effects of ICS are rare and usually trivial, our study shows that young children will be exposed to higher dose of drug in the pharynx.

Budesonide is readily absorbed from the nasal mucosa, and will contribute to the systemic dose (21). The youngest group of children aged 2-3 yr inhaled the aerosol via facemask instead of mouthpiece. This allows nasal breathing, which may reduce the lung dose due to filtering in the nose, though this filter effect seems inversely related to age, that is, the nasal deposition is less in young children as compared with older children (22). We did not separate nasal and lung contribution to the systemic dose, and therefore we cannot estimate the effect of facemask on the lung dose. However, the systemic exposure (pl-concentration) was similar in 2- to 3-yr-old children with a facemask and 4- to 6-yr-old children using a mouthpiece. Therefore, from a systemic safety perspective, a mouthpiece or facemask can be used interchangeably.

In conclusion, the present data suggest that inhalation of budesonide from a pMDI and Nebuchamber spacer provides increasing lung dose with age as the systemic exposure (drug pl-concentration) was found to be similar in young children and adults. These findings indicate that from a safety perspective, similar doses may be prescribed in children and adults. This observation is reassuring as the prescription of doses close to recommended adult doses is often required in pediatric asthma management, which has been cause for concern due to the widely held belief that the drug concentration in the child would be high. This concern may have had the effect that children have been given too low and therapeutically nonoptimal doses. The present observation may call for a revision of the present dose recommendations in pediatric asthma management.