Age dependent systemic exposure to inhaled salbutamol

Abstract

What is already known about this subject

• There is only scant evidence on how to adjust the dose of inhaled drugs in children.

• Salbutamol delivered via a pressurized metered dose inhaler (pMDI) with spacer is one of the most commonly used anti-asthmatic treatments in children but the effect of age on systemic exposure following this treatment has not previously been investigated.

What this study adds

• The present study shows that prescribing salbutamol from a pMDI with spacer as a fixed dose kg⁻¹ causes reduced exposure in young children with a corresponding risk of unnecessary suboptimal dosing.

• On the other hand a fixed absolute dose causes some over-dosing in young children.

• The study underlines that research into the dosage regimens of aerosol treatment for children is needed to assure evidence based optimal treatment.

Aims

To determine the effect of age on systemic exposure to inhaled salbutamol in children.

Methods

Fifty-eight asthmatic children, aged 3–16 years, inhaled 400 µg of salbutamol from a pressurized metered dose inhaler with spacer. The 20 min serum profile was analyzed.

Results

Prescribing a dose on a µg kg⁻¹ basis caused reduced systemic exposure in young children (Y) compared with older children (O) (C_{max -µgkg⁻¹-adjusted}Y : O ratio (95%CI) = 0.55 (0.47, 0.65)) whereas a fixed nominal dose irrespective of age caused increased exposure in young children (C_max Y : O ratio (95%CI) = 1.7 (1.3, 2.2)).

Conclusions

For similar systemic exposure, dosing should be adjusted to age or size but not on a fixed µg kg⁻¹ basis, which may lead to unnecessary suboptimal dosing.

Introduction

Paediatric dosing traditionally adjusts for age (size) to assure age (size) independent systemic exposure. However in inhalation therapy such dose adjustment is based on scant evidence and may be inappropriate. In a previous study we reported similar systemic exposure inchildren and adults inhaling the same nominal doses of budesonide from a pressurized metered dose inhaler (pMDI) and spacer [1]. Young children are probably protected from excessive systemic exposure by a reduced lung dose [2–7], and lung dose is an important contributor to systemic exposure for inhaled drugs such as β₂-adrenoceptor agonists and inhaled corticosteroids. Also differences in pharmacokinetics, e.g. increased relative clearance, may cause reduced exposure in children [6]. Therefore the systemic exposure in younger individuals may be smaller than expected from their body size and the common practice of reducing the dose in young children for fear of excessive systemic exposure may cause unnecessary subeffective dosing.

Systemic exposure to inhaled drugs determines risk of systemic side-effects and is therefore one relevant measure of drug exposure. Systemic exposure should be studied for individual drugs because the effect of age on pharmacokinetics may differ between drugs. We therefore performed a study of the systemic exposure (safety) of salbutamol inhaled from a pMDI and spacer in different age groups.

Methods

Patients

Children aged 2–15 years, with a history of mild to moderate asthma which was currently stable, were included in the study. Written informed consent was obtained from a parent or legal guardian. The child gave verbal assent. The study was approved by the Danish Medicine Agency (2612–1071) and the Ethics Committee of Copenhagen (KF.02–079/99).

Drug administration

The study was of an open design. Any β₂-adrenoceptor agonist treatment was stopped 48 h before the study day. 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 nonelectrostatic metal spacer (Nebuchamber; AstraZeneca) [8, 9]. All children inhaled from the spacer mouthpiece using a nose clip (no one used a face mask). The pMDI was primed (four puffs) before inhalation and shaken thoroughly immediately before each actuation. A total nominal dose of 400 µg salbutamol was administered (four doses of 100 µg with an interval of 10 inspirations). Before inhalation, a catheter (Venflon 2 0.8/25 mm; Ohmeda AB) was inserted into a forearm vein. The skin was anaesthetized using EMLA cream. Blood samples were collected before and 5, 10, 15 and 20 min after inhalation. Serum was transferred to polystyrene tubes, and stored at −80 °C until analysis.

Lung function was measured before inhalation of salbutamol as the forced expiratory volume after 1 s (FEV₁) in older children and specific airways resistance (sRaw) in all of the children.

Drug analysis

Serum samples were analyzed at 3M laboratories, USA. Serum (500 µl) was extracted using 3M Empore C8 cartridges. The extract was concentrated and injected into a high performance liquid chromatography/mass spectroscopy/mass spectroscopy system (Sciex API 3000 with turbo ion interface). The high performance liquid chromatography was a Zorbax Bonus-RP.

The lower limit of quantification was 25.4 pg ml⁻¹, the linear range for salbutamol detection in serum was 25.4 pg ml⁻¹ to 5070 pg ml^– and the coefficient of variation was 14.8%.

Statistical analysis

Maximum observed serum concentration (C_max) and time to C_max (t_max) were observed directly from the concentration data. C_max adjusted for differences in the inhaled µg kg⁻¹ dose (C_{max -µgkg⁻¹-adjusted}) was calculated.

The relationship between C_max, C_{max -µgkg⁻¹-adjusted} and age/body size was first analyzed using multiple regression analysis. However the predictor variables were highly correlated and the models could be reduced to simple linear models with weight and age as predictors for C_max and C_{max -µgkg⁻¹-adjusted}, respectively. The assumptions for the regression analysis were checked by visual inspection of normal plots of residuals and plots of residuals vs. fitted values. A logarithmic scale was appropriate for C_max.

95% confidence intervals (CI) for young : older children ratios were calculated from the linear regression models.

Results

Sixty-five patients were enrolled in the study and 58 (age range 3–16 years) completed the study. Four children were excluded due to difficulties establishing intravenous access. Three were excluded before blood sampling due to incorrect inhalation technique (wrong instructions given by clinical assistant). Two patients weighing 78 and 111 kg, respectively, were excluded as outliers from the statistical analysis, since there was insufficient data to draw conclusions about systemic exposure in this weight-group. This left 56 subjects for statistical analysis.

No adverse events were reported during the study.

Eight children could not perform the FEV₁-measurement including five out of six children aged 3–4 years. Three children did not provide sRaw data.

Mean FEV₁ was 96% predicted [10] and mean sRaw was 1.22 kPa s⁻¹ (94% predicted) [11]. There was no correlation between lung function before inhalation (% FEV₁ or sRaw) and C_max or C_{max -µgkg⁻¹-adjusted}.

Serum concentrations of salbutamol were below the lower limit of quantification at time 0 h for all subjects but one, whose serum concentration was 32 pg ml⁻¹ and considered negligible.

Median (range) t_max was 15 min (range 5–20 min). In eleven subjects t_max occurred at 20 min. There was no correlation between t_max and height, weight or age. There was a significant negative correlation between C_max and weight (P< 0.0001) (Figure 1). The C_max ratio for young children (20 kg) : older children (60 kg) was 1.7 (95% CI 1.3, 2.2).

Figure 1.

C_max vs. weight. Regression line (log(y) = −0.00555x + 0.53) and 95% confidence interval for the regression. r² = 0.224

There was a significant positive correlation between C_{max -µgkg⁻¹-adjusted} and age (P< 0.0001) (Figure 2). The C_{max -µgkg⁻¹-adjusted} ratio for young children (5 years) : older children (15 years) was 0.55 (95% CI 0.47, 0.65).

Figure 2.

C_max adjusted for differences in inhaled µg kg⁻¹ dose (C_max/(400 µg weight⁻¹) × (400 µg/62 kg)) vs. age. Regression line (y = 70.8x + 515) and 95% confidence interval for the regression, r² = 0.366

Discussion

The nature of side-effects may differ between drugs and therefore different study designs are required for different drugs. For steroids it is assumed that the risk of side-effects is best predicted by the total systemic exposure measured as area under the curve. For β₂-adrenoceptor agonists the risk of side-effects is more closely related to peak concentrations of the drug. Side-effects of inhaled β₂-adrenoceptor agonists are mediated by extrapulmonary β₂-adrenoceptors. They include finger tremor, hypokalaemia, electrocardiographic sequelae and chrontropic and inotropic responses and they occur in a linear dose-dependent manner [12]. Systemic concentrations of salbutamol are known to peak approximately 10 min after inhalation [13, 14] and maximal systemic effects occur at approximately 30 min after inhalation [15]. This suggests that the risk of side-effects from inhaled salbutamol is related to the maximal systemic concentration reached shortly after inhalation of drug. We therefore measured serum concentrations for the first 20 min after inhalation.

In this study all children inhaled a fixed nominal dose of 400 µg irrespective of age and therefore younger age groups received higher doses relative to body size. This resulted in higher systemic exposure in younger (smaller) children compared with older children (Figure 1) with a corresponding increased risk of side-effects. Lung function (% predicted) did not confound this relationship [16]. This is in contrast to a study with budesonide [1] where a fixed dose regimen seemed appropriate for similar systemic exposure, irrespective of age, and underlines the fact that systemic exposure must be studied for individual drugs.

Since the pharmacokinetics of salbutamol after inhalation show linearity [17], we can calculate the serum concentrations reached if the children inhaled the same µg kg⁻¹ dose (C_{max -µgkg⁻¹-adjusted}) (Figure 2). This would result in approximately 50% lower serum concentrationsin younger children compared with older children and such dosing may lead to unnecessary suboptimal treatment.

The amount of salbutamol that reaches the circulation in the first 20 min after inhalation reflects early lung bio-availability since the gastrointestinal contribution at this time period is negligible [18, 19]. Therefore, in the present study, serum concentrations of salbutamol adjusted for differences in µg kg⁻¹ dose (C_{max -µgkg⁻¹-adjusted}) provide an index of the fraction of drug reaching the lungs (= lung dose). Our study suggests that lung dose is reduced by approximately 50% in the youngest children. However, since we compared children from different age groups, this association could also be due to differences in pharmacokinetics, e.g. a higher volume of distribution per kg of body weight in younger children. Because of the multicompartmental behaviour of salbutamol [14], the parameters determining systemic concentrations in the first 20 min after inhalation are the rate of absorption, the initial volume of distribution and the rate of transfer between compartments. We have found no data on these parameters in children in the literature. In the present study there was no significant correlation between age/body size and t_max indicating that there was no significant difference in the rate of absorption between the age groups, but this requires further study.

In conclusion, for similar systemic exposure irrespective of age, dosing with salbutamol from a pMDI and spacer should be adjusted to age or size but not be on a fixed µg kg⁻¹ basis which causes reduced exposure in young children with a corresponding risk of unnecessary suboptimal dosing. This could be due to reduced lung deposition in younger children, differences in pharmacokinetics or both. Research into the dosage regimens of aerosol treatment of children is needed to assure evidence based optimal treatment for children.