British Journal of Clinical Pharmacology
Age dependent systemic exposure to inhaledsalbutamol
Klaus Bønnelykke, Jakob Jessing Jespersen & Hans BisgaardDanish Pediatric Asthma Center; Copenhagen University Hospital, Gentofte, DK-2900 Copenhagen, Denmark
What is already known about this subject
What this study adds
• There is only scant evidence on how to adjust the dose
• The present study shows that prescribing salbutamol from a
of inhaled drugs in children.
pMDI with spacer as a fixed dose kg-1 causes reduced
• Salbutamol delivered via a pressurized metered dose
exposure in young children with a corresponding risk of
inhaler (pMDI) with spacer is one of the most commonly
unnecessary suboptimal dosing.
used anti-asthmatic treatments in children but the effect
• On the other hand a fixed absolute dose causes some
of age on systemic exposure following this treatment has
over-dosing in young children.
not previously been investigated.
• The study underlines that research into the dosage regimens
of aerosol treatment for children is needed to assureevidence based optimal treatment.
Dr Klaus Bønnelykke, Danish
To determine the effect of age on systemic exposure to inhaled salbutamol in children.
Pediatric Asthma Center, Departmentof Pediatrics, Copenhagen University
Hospital, Gentofte, DK-2900
Fifty-eight asthmatic children, aged 3–16 years, inhaled 400 mg of salbutamol from a
pressurized metered dose inhaler with spacer. The 20 min serum profile was analyzed.
Tel.: + 45 3977 7362Fax: + 45 3977 7129
Prescribing a dose on a mg kg-1 basis caused reduced systemic exposure in youngchildren (Y) compared with older children (O) ( Cmax
(95%CI) = 0.55 (0.47, 0.65)) whereas a fixed nominal dose irrespective of age causedincreased exposure in young children (Cmax
Y : O ratio (95%CI) = 1.7 (1.3, 2.2)).
Keywordsaerosols, asthma, children,
For similar systemic exposure, dosing should be adjusted to age or size but not on afixed mg kg-1 basis, which may lead to unnecessary suboptimal dosing.
Received24 February 2006Accepted18 December 2006Published OnlineEarly
1 March 2007
However in inhalation therapy such dose adjustment is
Paediatric dosing traditionally adjusts for age (size) to
based on scant evidence and may be inappropriate. In a
assure age (size) independent systemic exposure.
previous study we reported similar systemic exposure in
2007 The Authors
Br J Clin Pharmacol
Journal compilation 2007 Blackwell Publishing Ltd
K. Bønnelykke et al.
children and adults inhaling the same nominal doses of
after inhalation. Serum was transferred to polystyrene
budesonide from a pressurized metered dose inhaler
tubes, and stored at -80 °C until analysis.
(pMDI) and spacer . Young children are probably
Lung function was measured before inhalation of
protected from excessive systemic exposure by a
salbutamol as the forced expiratory volume after 1 s
reduced lung dose [2–7], and lung dose is an important
(FEV1) in older children and specific airways resistance
contributor to systemic exposure for inhaled drugs such
(sRaw) in all of the children.
as b2-adrenoceptor agonists and inhaled corticosteroids.
Also differences in pharmacokinetics, e.g. increased
relative clearance, may cause reduced exposure in chil-
Serum samples were analyzed at 3M laboratories, USA.
dren . Therefore the systemic exposure in younger
Serum (500 ml) was extracted using 3M Empore C8
individuals may be smaller than expected from their
cartridges. The extract was concentrated and injected
body size and the common practice of reducing the dose
into a high performance liquid chromatography/mass
in young children for fear of excessive systemic expo-
spectroscopy/mass spectroscopy system (Sciex API
sure may cause unnecessary subeffective dosing.
3000 with turbo ion interface). The high performance
Systemic exposure to inhaled drugs determines risk of
liquid chromatography was a Zorbax Bonus-RP.
systemic side-effects and is therefore one relevant
The lower limit of quantification was 25.4 pg ml-1, the
measure of drug exposure. Systemic exposure should be
linear range for salbutamol detection in serum was
studied for individual drugs because the effect of age on
25.4 pg ml-1 to 5070 pg ml– and the coefficient of varia-
pharmacokinetics may differ between drugs. We there-
tion was 14.8%.
fore performed a study of the systemic exposure (safety)of salbutamol inhaled from a pMDI and spacer in dif-
ferent age groups.
Maximum observed serum concentration (Cmax
) and timeto Cmax
max) were observed directly from the concentra-
tion data. Cmax
adjusted for differences in the inhaled
g kg-1 dose (Cmax
µ kg−1−adjusted) was calculated.
The relationship between C
Children aged 2–15 years, with a history of mild to
µ kg −adjusted
age/body size was first analyzed using multiple regres-
moderate asthma which was currently stable, were
sion analysis. However the predictor variables were
included in the study. Written informed consent was
highly correlated and the models could be reduced to
obtained from a parent or legal guardian. The child gave
simple linear models with weight and age as predictors
verbal assent. The study was approved by the Danish
, respectively. The assump-
Medicine Agency (2612–1071) and the Ethics Commit-
µ kg −adjusted
tions for the regression analysis were checked by visual
tee of Copenhagen (KF.02–079/99).
inspection of normal plots of residuals and plots ofresiduals vs.
fitted values. A logarithmic scale was
appropriate for Cmax
The study was of an open design. Any b2-adrenoceptor
95% confidence intervals (CI) for young : older chil-
agonist treatment was stopped 48 h before the study day.
dren ratios were calculated from the linear regression
The children were trained in the inhalation technique
and each administration was monitored. Rac-salbutamol(Airomir; 3M Health Care) was administered as an
aerosol via a pMDI (non-CFC) and a 250 ml nonelec-
Sixty-five patients were enrolled in the study and 58 (age
trostatic metal spacer (Nebuchamber; AstraZeneca) [8,
range 3–16 years) completed the study. Four children
9]. All children inhaled from the spacer mouthpiece
were excluded due to difficulties establishing intrave-
using a nose clip (no one used a face mask). The pMDI
nous access. Three were excluded before blood sam-
was primed (four puffs) before inhalation and shaken
pling due to incorrect inhalation technique (wrong
thoroughly immediately before each actuation. A total
instructions given by clinical assistant). Two patients
nominal dose of 400 mg salbutamol was administered
weighing 78 and 111 kg, respectively, were excluded as
(four doses of 100 mg with an interval of 10 inspira-
outliers from the statistical analysis, since there was
tions). Before inhalation, a catheter (Venflon 2 0.8/
insufficient data to draw conclusions about systemic
25 mm; Ohmeda AB) was inserted into a forearm vein.
exposure in this weight-group. This left 56 subjects for
The skin was anaesthetized using EMLA cream. Blood
samples were collected before and 5, 10, 15 and 20 min
No adverse events were reported during the study.
Br J Clin Pharmacol
10 15 20 25 30 35 40 45 50 55 60 65
adjusted for differences in inhaled mg kg-1 dose
weight. Regression line (log(y) = -0.00555x + 0.53) and 95%
confidence interval for the regression. r
2 = 0.224
/(400 mg weight-1) ¥ (400 mg/62 kg)) vs.
age. Regression line(y
= 70.8x + 515) and 95% confidence interval for the regression,r
2 = 0.366
Eight children could not perform the FEV1-
measurement including five out of six children aged
effects of inhaled b2-adrenoceptor agonists are mediated
3–4 years. Three children did not provide sRaw data.
by extrapulmonary b2-adrenoceptors. They include
Mean FEV1 was 96% predicted  and mean sRaw
was 1.22 kPa s-1 (94% predicted) . There was no
sequelae and chrontropic and inotropic responses and
correlation between lung function before inhalation (%
they occur in a linear dose-dependent manner . Sys-
FEV1 or sRaw) and Cmax
temic concentrations of salbutamol are known to peak
Serum concentrations of salbutamol were below the
approximately 10 min after inhalation [13, 14] and
lower limit of quantification at time 0 h for all subjects
maximal systemic effects occur at approximately 30 min
but one, whose serum concentration was 32 pg ml-1 and
after inhalation . This suggests that the risk of side-
effects from inhaled salbutamol is related to the maximal
Median (range) tmax
was 15 min (range 5–20 min). In
systemic concentration reached shortly after inhalation
eleven subjects tmax
occurred at 20 min. There was no
of drug. We therefore measured serum concentrations
correlation between tmax
and height, weight or age. There
for the first 20 min after inhalation.
was a significant negative correlation between Cmax
In this study all children inhaled a fixed nominal dose
< 0.0001) (Figure 1). The Cmax
ratio for young
of 400 mg irrespective of age and therefore younger age
children (20 kg) : older children (60 kg) was 1.7 (95%
groups received higher doses relative to body size. This
CI 1.3, 2.2).
resulted in higher systemic exposure in younger
There was a significant positive correlation between
(smaller) children compared with older children
µ kg−1−adjusted and age (P
< 0.0001) (Figure 2). The
(Figure 1) with a corresponding increased risk of side-
µ kg−1−adjusted ratio for young children (5 years) :
effects. Lung function (% predicted) did not confound
older children (15 years) was 0.55 (95% CI 0.47, 0.65).
this relationship . This is in contrast to a study withbudesonide  where a fixed dose regimen seemed
appropriate for similar systemic exposure, irrespective
The nature of side-effects may differ between drugs and
of age, and underlines the fact that systemic exposure
therefore different study designs are required for differ-
must be studied for individual drugs.
ent drugs. For steroids it is assumed that the risk of
Since the pharmacokinetics of salbutamol after inha-
side-effects is best predicted by the total systemic
lation show linearity , we can calculate the serum
exposure measured as area under the curve. For
concentrations reached if the children inhaled the same
2-adrenoceptor agonists the risk of side-effects is more
g kg-1 dose (Cmax
µ kg−1−adjusted) (Figure 2). This would
closely related to peak concentrations of the drug. Side-
result in approximately 50% lower serum concentrations
Br J Clin Pharmacol
K. Bønnelykke et al.
in younger children compared with older children and
metered-dose inhaler with holding chamber? In vivo
such dosing may lead to unnecessary suboptimal
of lung deposition in children. J Pediatr 1999; 135: 28–33.
3 Wildhaber JH, Janssens HM, Pierart F, Dore ND, Devadason SG,
The amount of salbutamol that reaches the circulation
LeSouef PN. High-percentage lung delivery in children from
in the first 20 min after inhalation reflects early lung
detergent-treated spacers. Pediatr Pulmonol 2000; 29: 389–93.
bio-availability since the gastrointestinal contribution at
4 Tal A, Golan H, Grauer N, Aviram M, Albin D, Quastel MR.
this time period is negligible [18, 19]. Therefore, in the
Deposition pattern of radiolabeled salbutamol inhaled from a
present study, serum concentrations of salbutamol
metered-dose inhaler by means of a spacer with mask in youngchildren with airway obstruction. J Pediatr 1996; 128: 479–84.
adjusted for differences in mg kg-1 dose (Cmax
µ kg−1−adjusted )
5 Zar HJ, Weinberg EG, Binns HJ, Gallie F, Mann MD. Lung
provide an index of the fraction of drug reaching the
deposition of aerosol – a comparison of different spacers. Arch
lungs (= lung dose). Our study suggests that lung dose is
Dis Child 2000; 82: 495–8.
reduced by approximately 50% in the youngest children.
6 Agertoft L, Andersen A, Weibull E, Pedersen S. Systemic
However, since we compared children from different age
availability and pharmacokinetics of nebulised budesonide in
groups, this association could also be due to differences
preschool children. Arch Dis Child 1999; 80: 241–7.
in pharmacokinetics, e.g. a higher volume of distribution
7 Chua HL, Collis GG, Newbury AM, Chan K, Bower GD, Sly PD,
per kg of body weight in younger children. Because of
Le Souef PN. The influence of age on aerosol deposition in
the multicompartmental behaviour of salbutamol ,
children with cystic fibrosis. Eur Respir J 1994; 7: 2185–91.
the parameters determining systemic concentrations in
8 Bisgaard H, Anhoj J, Klug B, Berg E. A non-electrostatic spacer
the first 20 min after inhalation are the rate of absorp-
for aerosol delivery. Arch Dis Child 1995; 73: 226–30.
tion, the initial volume of distribution and the rate of
9 Bisgaard H. A metal aerosol holding chamber devised for young
transfer between compartments. We have found no data
children with asthma. Eur Respir J 1995; 8: 856–60.
on these parameters in children in the literature. In the
10 Quanjer PH, Stocks J, Polgar G, Wise M, Karlberg J, Borsboom
present study there was no significant correlation
G. Compilation of reference values for lung function
between age/body size and tmax
indicating that there was
measurements in children. Eur Respir J Suppl 1989; 4:
no significant difference in the rate of absorption
between the age groups, but this requires further study.
11 Klug B, Bisgaard H. Specific airway resistance, interrupter
In conclusion, for similar systemic exposure irrespec-
resistance, and respiratory impedance in healthy children aged
tive of age, dosing with salbutamol from a pMDI and
2–7 years. Pediatr Pulmonol 1998; 25: 322–31.
spacer should be adjusted to age or size but not be on a
12 Lipworth BJ. Risks versus
benefits of inhaled beta 2-agonists in
fixed mg kg-1 basis which causes reduced exposure in
the management of asthma. Drug Safety 1992; 7: 54–70.
young children with a corresponding risk of unnecessary
13 Newnham DM, McDevitt DG, Lipworth BJ. Comparison of the
suboptimal dosing. This could be due to reduced lung
extrapulmonary b -adrenoceptor responses and
deposition in younger children, differences in pharma-
pharmacokinetics of salbutamol given by standard metereddose-inhaler and modified actuator device. Br J Clin Pharmacol
cokinetics or both. Research into the dosage regimens of
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14 Anderson PJ, Zhou X, Breen P, Gann L, Logsdon TW, Compadre
dence based optimal treatment for children.
CM, Hiller FC. Pharmacokinetics of (R,S)-albuterol after aerosolinhalation in healthy adult volunteers. J Pharm Sci 1998; 87:
Study medication and serum analysis were sponsored by
15 Rahman AR, McDevitt DG, Struthers AD, Lipworth BJ. Sex
Competing interests: HB has been a consultant to,
differences in hypokalaemic and electrocardiographic effects of
paid lecturer for and holds sponsored grants from Aero-
inhaled terbutaline. Thorax 1992; 47: 1056–9.
crine, AstraZeneca, Altana, GSK, MedImmune and
16 Lipworth BJ, Clark DJ. Effects of airway calibre on lung delivery
Merck. He does not hold stock or options in any phar-
of nebulised salbutamol. Thorax 1997; 52: 1036–9.
maceutical company in the respiratoty field.
17 Newnham DM, Lipworth BJ. Nebuliser performance,
pharmacokinetics, airways and systemic effects of salbutamolgiven via a novel nebuliser delivery system (Ventstream). Thorax
1994; 49: 762–70.
1 Anhoj J, Thorsson AL, Bisgaard H. Lung deposition of inhaled
18 Hindle M, Chrystyn H. Determination of the relative
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2 Wildhaber JH, Dore ND, Wilson JM, Devadason SG, LeSouef PN.
19 Lipworth BJ. Pharmacokinetics of inhaled drugs. Br J Clin
Inhalation therapy in asthma: nebulizer or pressurized
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