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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 Hellerup, Denmark.
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-µgkg−1 (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 OnlineEarly1 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 [1]. 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 Drug analysis relative clearance, may cause reduced exposure in chil- Serum samples were analyzed at 3M laboratories, USA.
dren [6]. 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 (tmax) were observed directly from the concentra- tion data. Cmax adjusted for differences in the inhaled g kg-1 dose (Cmax- g µ kg−1−adjusted) was calculated.
The relationship between C Children aged 2–15 years, with a history of mild to max, Cmax- g 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- max and Cmax- g 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 Cmax (pg/ml)
10 15 20 25 30 35 40 45 50 55 60 65
Weight (kg)
Age (years)
Cmax adjusted for differences in inhaled mg kg-1 dose max vs. weight. Regression line (log(y) = -0.00555x + 0.53) and 95% confidence interval for the regression. r2 = 0.224 (Cmax/(400 mg weight-1) ¥ (400 mg/62 kg)) vs. age. Regression line(y = 70.8x + 515) and 95% confidence interval for the regression,r2 = 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 [10] and mean sRaw was 1.22 kPa s-1 (94% predicted) [11]. There was no sequelae and chrontropic and inotropic responses and correlation between lung function before inhalation (% they occur in a linear dose-dependent manner [12]. Sys- FEV1 or sRaw) and Cmax or Cmax- g 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 [15]. 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 and In this study all children inhaled a fixed nominal dose weight (P < 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 [16]. This is in contrast to a study withbudesonide [1] 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 [17], 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- g 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 comparison 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- g 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 [14], 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 1993; 36: 445–50.
aerosol treatment of children is needed to assure evi- 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 3M Pharma. 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 drugs increases with age [In Process Citation]. Am J Respir Crit bioavailability of salbutamol to the lung following inhalation. Br J Care Med 2000; 162: 1819–22.
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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 Pharmacol 1996; 42: 697–705.
Br J Clin Pharmacol

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